rs72474224

chr13-20189473-C-Achr13-20189473-C-T

• Frequency: Genomes: not found (cov: 33)
• Consequence: GJB2 NM_004004 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 6.10

ACMG classification

Verdict is Pathogenic. Variant got 17 ACMG points.

• PM1: In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in NM_004004
• PM2: Very rare variant; Number of alleles below threshold, Median coverage is 33.
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr13-20189472-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 449490. Status of the report is reviewed_by_expert_panel, 3 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.972
• PP5: Variant 13:20189473-C>A is Pathogenic according to our data. Variant chr13-20189473-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 179256. Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GJB2	NM_004004.6	c.109G>T	p.Val37Phe	missense_variant	2/2	ENST00000382848.5
GJB2	XM_011535049.3	c.109G>T	p.Val37Phe	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GJB2	ENST00000382848.5	c.109G>T	p.Val37Phe	missense_variant	2/2	1	NM_004004.6	P1
GJB2	ENST00000382844.2	c.109G>T	p.Val37Phe	missense_variant	1/1			P1

Frequencies

GnomAD3 genomes Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

LINK:

Submissions by phenotype

Rare genetic deafness Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Oct 05, 2013

The Val37Phe variant in GJB2 has not been previously reported in individuals wit h hearing loss or in large population studies; however it was identified in tran s (on separate copies of the gene) with the 167delT pathogenic variant in this i ndividual by our laboratory. In addition, a known pathogenic variant at the same amino acid position (Val37Ile) has been reported in individuals with hearing lo ss that is typically mild to moderate (Snoeckx 2005, Huculak 2006, Pollak 2007). In summary, this variant is likely to be pathogenic because it is found in tran s with a pathogenic GJB2 variant in an affected individual and it alters the sam e amino acid residue affected by a known pathogenic GJB2 variant; however, addit ional studies are required to fully establish its clinical significance. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Aug 23, 2022

This sequence change replaces valine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 37 of the GJB2 protein (p.Val37Phe). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with GJB2-related conditions. ClinVar contains an entry for this variant (Variation ID: 179256). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GJB2 protein function. This variant disrupts the p.Val37 amino acid residue in GJB2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12505163, 17935238, 24945352, 28489599). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.47

BayesDel_addAF

Pathogenic

0.50

D

BayesDel_noAF

Pathogenic

0.48

Cadd

Uncertain

24

Dann

Uncertain

0.99

DEOGEN2

Pathogenic

0.85

D;D;D

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Uncertain

0.97

D

M_CAP

Pathogenic

0.39

D

MetaRNN

Pathogenic

0.97

D;D;D

MetaSVM

Pathogenic

1.1

D

MutationAssessor

Uncertain

2.8

M;M;M

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.59

T

PROVEAN

Uncertain

-4.3

D;D;.

REVEL

Pathogenic

0.83

Sift

Benign

0.13

T;T;.

Sift4G

Benign

0.32

T;T;.

Polyphen

1.0

D;D;D

Vest4

0.89

MutPred

0.81

Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);

MVP

0.93

MPC

0.31

ClinPred

1.0

D

GERP RS

5.2

Varity_R

0.77

gMVP

0.97

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs72474224; hg19: chr13-20763612;