Related Experiment Video

Updated: Apr 14, 2026

Determining the Likelihood of Variant Pathogenicity Using Amino Acid-level Signal-to-Noise Analysis of Genetic Variation

Determining the Likelihood of Variant Pathogenicity Using Amino Acid-level Signal-to-Noise Analysis of Genetic Variation

Published on: January 16, 2019

Assessing Allele Frequency Information: A Study of Variant Curation Expert Panel Guidelines

Xiaoyan Wang¹, Tongmei Zhang², Yayun Qin¹

¹Medical Genetics Center, Maternal and Child Health Hospital of Hubei Province, Wuhan, China.

|April 13, 2026

Abstract

Purpose:

The 2015 guidelines recommend using a large, diverse, and race-matched reference database. However, defining expectations in this context is subjective due to factors like genetic diversity and penetrance. ClinGen forms VCEPs to provide gene-specific interpretations of ACMG/AMP guidelines, including population information. Our study evaluates VCEP guidelines on allele frequency information.

Methods:

We analyzed genetic codes in databases to determine the frequency and potential pathogenicity of variants among 39 VCEPs, considering factors like allele frequency thresholds and disease prevalence.

Results:

Our analysis found a variety of approved cutoffs among VCEPs, showing diverse disease mechanisms. We also noted variability in methods used to establish cutoffs and inconsistencies in parameters deemed necessary for approved thresholds.

Conclusions:

Understanding thresholds requires knowledge of genetics and diseases. VCEP guidelines on allele frequency evidence can help curators identify recommended thresholds. However, more guidance is needed for consistency in population evidence utilization.

More Related Videos

Rare Event Detection Using Error-corrected DNA and RNA Sequencing

Rare Event Detection Using Error-corrected DNA and RNA Sequencing

Published on: August 3, 2018

Targeted Next-generation Sequencing and Bioinformatics Pipeline to Evaluate Genetic Determinants of Constitutional Disease

Targeted Next-generation Sequencing and Bioinformatics Pipeline to Evaluate Genetic Determinants of Constitutional Disease

Published on: April 4, 2018

Related Concept Videos

Hardy-Weinberg Principle

Hardy-Weinberg Principle

Diploid organisms have two alleles of each gene, one from each parent, in their somatic cells. Therefore, each individual contributes two alleles to the gene pool of the population. The gene pool of a population is the sum of every allele of all genes within that population and has some degree of variation. Genetic variation is typically expressed as a relative frequency, which is the percentage of the total population that has a given allele, genotype or phenotype.

Comparing Copy Number Variations and SNPs

Comparing Copy Number Variations and SNPs

Sequencing of the human genome has opened up several best-kept secrets of the genome. Scientists have identified thousands of genome variations that exist within a population. These variations can be a single nucleotide or a larger chromosomal variation.
Copy number variations or CNVs are the structural variations that cover more than 1kb of DNA sequence. The single nucleotide polymorphism (SNP), on the other hand, is a single nucleotide change or a point mutation that is found in more than 1%...

Genetic Variation

Genetic Variation

Genetic variation is the diversity in DNA sequences found among individuals of the same species. This diversity is crucial for a species' survival because it helps organisms adapt to environmental changes. Genetic variation begins with fertilization, where an egg and sperm cell merge. Each of these cells carries 23 chromosomes, up to 46 in the fertilized egg. Chromosomes are long DNA strands that contain genes, the basic units of heredity.
Genes exist in different versions called alleles,...

What is Population Genetics?

What is Population Genetics?

A population is composed of members of the same species that simultaneously live and interact in the same area. When individuals in a population breed, they pass down their genes to their offspring. Many of these genes are polymorphic, meaning that they occur in multiple variants. Such variations of a gene are referred to as alleles. The collective set of all the alleles within a population is known as the gene pool.

Mutation, Gene Flow, and Genetic Drift

Mutation, Gene Flow, and Genetic Drift

In a population that is not at Hardy-Weinberg equilibrium, the frequency of alleles changes over time. Therefore, any deviations from the five conditions of Hardy-Weinberg equilibrium can alter the genetic variation of a given population. Conditions that change the genetic variability of a population include mutations, natural selection, non-random mating, gene flow, and genetic drift (small population size).

Cis-regulatory Sequences

Cis-regulatory Sequences

Cis-regulatory sequences are short fragments of non-coding DNA that are present on the same chromosomes as the genes that they regulate. These fragments serve as binding sites for transcriptional regulators, proteins that are responsible for controlling gene transcription and differential gene expression across cell types in eukaryotes. Cis-regulatory sequences can be close to the gene of interest or thousands of bases away in the DNA sequence; however, those sequences that are further away are...

Articles linked to this work by shared authors, journal, and citation graph.

The Asymmetric Threat of Maternal Cell Contamination in Prenatal Single-Gene Testing.

Diagnostics (Basel, Switzerland)·2026

A Multicenter Integrative Cohort Characterizing the Genetic, Clinical, and Transcriptomic Features of ACP5 Deficiency.

Arthritis & rheumatology (Hoboken, N.J.)·2026

The added value of whole-exome sequencing for fetuses with postural defects by prenatal ultrasound.

International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics·2026

Genomic Landscape and Perinatal Outcomes of Fetal Polydactyly: A Retrospective Cohort Study Integrating CNV-seq and Trio-ES.

Prenatal diagnosis·2026

Impact of NRSN2 deficiency on memory: Altered excitatory synaptic plasticity associated with reduced expression of NMDA receptor subunits and impaired LTP in the hippocampus.

Translational psychiatry·2026

PCYT1A Hypophosphorylation Underlies Retinal Lipid Dysregulation in CERKL Retinitis Pigmentosa and Is Therapeutically Reversed by Phosphatidylcholine.

Investigative ophthalmology & visual science·2026

See all related articles