rs886037849

Variant names:

• chr13-20189389-A-G
• rs886037849
• NM_004004.6:c.193T>C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP3_Strong PP5_Moderate

The NM_004004.6(GJB2):​c.193T>C​(p.Tyr65His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: GJB2 NM_004004.6 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 9.27

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]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM1: In a chain Gap junction beta-2 protein (size 225) in uniprot entity CXB2_HUMAN there are 70 pathogenic changes around while only 16 benign (81%) in NM_004004.6
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant 13-20189389-A-G is Pathogenic according to our data. Variant chr13-20189389-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 253134.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GJB2	NM_004004.6	c.193T>C	p.Tyr65His	missense_variant	Exon 2 of 2	ENST00000382848.5	NP_003995.2
GJB2	XM_011535049.3	c.193T>C	p.Tyr65His	missense_variant	Exon 2 of 2		XP_011533351.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GJB2	ENST00000382848.5	c.193T>C	p.Tyr65His	missense_variant	Exon 2 of 2	1	NM_004004.6	ENSP00000372299.4
GJB2	ENST00000382844.2	c.193T>C	p.Tyr65His	missense_variant	Exon 1 of 1	6		ENSP00000372295.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Pathogenic:1

Sep 21, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The GJB2 c.193T>C; p.Tyr65His variant (rs111033203), is reported in the literature in at least one individual affected with severe Vohwinkel syndrome and congenital sensory hearing impairment (de Zwart-Storm 2011). This variant is reported in ClinVar (Variation ID: 253134), and is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. The tyrosine at codon 65 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Additionally, another variant at this codon (c.194A>G, p.Tyr65Cys) has been reported in at least one individual with sensorineural hearing loss (Tayoun 2016). Codon 65 is located in the first extracellular domain of the protein, in which variants associated with autosomal dominant syndromic or nonsyndromic hearing loss cluster (Iossa 2011). In vitro functional analyses demonstrate mislocalization of the p.Tyr65His variant protein and reduced cellular gap junction function (de Zwart-Storm 2011). Based on available information, the p.Tyr65His variant is considered to be likely pathogenic. References: de Zwart-Storm EA et al. A novel missense mutation in GJB2, p.Tyr65His, causes severe Vohwinkel syndrome. Br J Dermatol. 2011 Jan;164(1):197-9. Iossa S et al. GJB2 Gene Mutations in Syndromic Skin Diseases with Sensorineural Hearing Loss. Curr Genomics. 2011 Nov;12(7):475-785. Tayoun AN et al. Targeted Droplet-Digital PCR as a Tool for Novel Deletion Discovery at the DFNB1 Locus. Hum Mutat. 2016 Jan;37(1):119-26. -

Mutilating keratoderma Pathogenic:1

Nov 01, 1997

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D;D;D
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	.;.;D
M_CAP	Pathogenic	0.76	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.6	H;H;H
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-4.8	D;D;.
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D;D;.
Sift4G	Pathogenic	0.0	D;D;.
Polyphen		1.0	D;D;D
Vest4		0.92
MutPred		0.93		Loss of ubiquitination at K61 (P = 0.0637);Loss of ubiquitination at K61 (P = 0.0637);Loss of ubiquitination at K61 (P = 0.0637);
MVP		0.99
MPC		0.31
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.93
gMVP		0.96

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

LitVar

Other links and lift over

dbSNP: rs886037849; hg19: chr13-20763528;