rs35887622

chr13-20189481-A-Cchr13-20189481-A-G

• Frequency: Genomes: not found (cov: 33)
• Consequence: GJB2 NM_004004 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 5.06

ACMG classification

Verdict is Pathogenic. Variant got 17 ACMG points.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 2 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 chr13-20189481-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 17000. Status of the report is reviewed_by_expert_panel, 3 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant 13:20189481-A>C is Pathogenic according to our data. Variant chr13-20189481-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 44722. 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.101T>G	p.Met34Arg	missense_variant	2/2	ENST00000382848.5
GJB2	XM_011535049.3	c.101T>G	p.Met34Arg	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GJB2	ENST00000382848.5	c.101T>G	p.Met34Arg	missense_variant	2/2	1	NM_004004.6	P1
GJB2	ENST00000382844.2	c.101T>G	p.Met34Arg	missense_variant	1/1			P1

Frequencies

GnomAD3 genomes Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK:

Submissions by phenotype

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 20, 2021	Reported in a patient with hearing loss in published literature (Putcha et al., 2007); however, clinical and molecular data were limited; Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Splice predictors and evolutionary conservation suggest this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 25388846, 17666888, 31589614) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	Aug 15, 2022	This sequence change replaces methionine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 34 of the GJB2 protein (p.Met34Arg). 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: 44722). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This variant disrupts the p.Met34 amino acid residue in GJB2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16077952, 22668073, 26117665; Invitae). 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. -

Rare genetic deafness Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 19, 2009

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.52

D

BayesDel_noAF

Pathogenic

0.51

Cadd

Pathogenic

27

Dann

Uncertain

0.98

DEOGEN2

Pathogenic

0.91

D;D;D

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Uncertain

0.95

D

M_CAP

Pathogenic

0.53

D

MetaRNN

Pathogenic

0.99

D;D;D

MetaSVM

Pathogenic

1.1

D

MutationAssessor

Uncertain

2.9

M;M;M

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.65

T

PROVEAN

Pathogenic

-4.5

D;D;.

REVEL

Pathogenic

0.92

Sift

Pathogenic

0.0

D;D;.

Sift4G

Pathogenic

0.0

D;D;.

Polyphen

0.98

D;D;D

Vest4

0.93

MutPred

0.98

Gain of methylation at M34 (P = 0.0182);Gain of methylation at M34 (P = 0.0182);Gain of methylation at M34 (P = 0.0182);

MVP

0.93

MPC

0.27

ClinPred

0.99

D

GERP RS

5.2

Varity_R

0.97

gMVP

0.98

Splicing

Name

Calibrated prediction

Score

Prediction

DS_AG_spliceai

0.58

Position offset: -1

DS_AL_spliceai

0.0

Position offset: -23

DS_DG_spliceai

0.0

Position offset: -1

DS_DL_spliceai

0.0

Position offset: -7

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

Publications

LitVar

Other links and lift over

dbSNP: rs35887622; hg19: chr13-20763620;