chr13-20188905-A-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_004004.6:c.677T>A variant in GJB2 is a missense variant predicted to cause substitution of valine by aspartic acid at amino acid 226 (p.Val226Asp). The variant was absent from gnomAD v2.1.1 meeting PM2_Supporting. The REVEL computational prediction analysis tool produced a score of 0.57 (PP3/BP4 not met). This variant has been identified in a heterozygous state in one individual with sensorineural hearing loss (PMID:20201936). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive nonsyndromic hearing loss. ACMG/AMP criteria applied as specified by the ClinGen Hearing Loss VCEP: PM2_Supporting (ClinGen Hearing Loss VCEP specifications version 2; 8/22/2023). LINK:https://erepo.genome.network/evrepo/ui/classification/CA387460663/MONDO:0019497/005

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

GJB2
NM_004004.6 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel U:1

Conservation

PhyloP100: 2.04

Publications

2 publications found

Variant links:

Genes affected

GJB2 (HGNC:4284): (gap junction protein beta 2) This gene encodes a member of the gap junction protein family. The gap junctions were first characterized by electron microscopy as regionally specialized structures on plasma membranes of contacting adherent cells. These structures were shown to consist of cell-to-cell channels that facilitate the transfer of ions and small molecules between cells. The gap junction proteins, also known as connexins, purified from fractions of enriched gap junctions from different tissues differ. According to sequence similarities at the nucleotide and amino acid levels, the gap junction proteins are divided into two categories, alpha and beta. Mutations in this gene are responsible for as much as 50% of pre-lingual, recessive deafness. [provided by RefSeq, Oct 2008]

GJB2 Gene-Disease associations (from GenCC):

Bart-Pumphrey syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
ichthyosis, hystrix-like, with hearing loss
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp
keratoderma hereditarium mutilans
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Genomics England PanelApp
palmoplantar keratoderma-deafness syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, G2P
syndromic genetic hearing loss
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
autosomal recessive nonsyndromic hearing loss 1A
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
nonsyndromic genetic hearing loss
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
autosomal dominant keratitis-ichthyosis-hearing loss syndrome
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Genomics England PanelApp
autosomal dominant nonsyndromic hearing loss 3A
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
autosomal dominant nonsyndromic hearing loss
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
KID syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
hearing loss, autosomal recessive
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

GJB2 links:

ENSG00000296095 (HGNC:):

ENSG00000296095 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004004.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GJB2	NM_004004.6	MANE Select	c.677T>A	p.Val226Asp	missense	Exon 2 of 2	NP_003995.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GJB2	ENST00000382848.5	TSL:1 MANE Select	c.677T>A	p.Val226Asp	missense	Exon 2 of 2	ENSP00000372299.4	P29033
GJB2	ENST00000382844.2	TSL:6	c.677T>A	p.Val226Asp	missense	Exon 1 of 1	ENSP00000372295.1	P29033
GJB2	ENST00000906230.1		c.677T>A	p.Val226Asp	missense	Exon 2 of 2	ENSP00000576289.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1460126

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726460

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33452

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.00

AC:

AN:

86238

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52456

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1111304

Other (OTH)

AF:

0.0000331

AC:

AN:

60360

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

Nonsyndromic genetic hearing loss (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.35

CADD

Benign

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.11

Eigen

Benign

-0.099

Eigen_PC

Benign

-0.021

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.82

M_CAP

Uncertain

0.24

MetaRNN

Pathogenic

0.89

MetaSVM

Uncertain

0.40

MutationAssessor

Benign

0.0

PhyloP100

2.0

PrimateAI

Uncertain

0.56

PROVEAN

Benign

0.60

REVEL

Uncertain

0.57

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0010

Polyphen

0.88

Vest4

0.60

MutPred

0.82

Loss of MoRF binding (P = 0.0211)

MVP

0.59

MPC

0.058

ClinPred

0.45

GERP RS

4.8

Varity_R

0.38

gMVP

0.92

Mutation Taster

=6/94

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over