13-20189095-T-G

Variant names:

• chr13-20189095-T-G
• rs80338949
• NM_004004.6:c.487A>C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PM5

The NM_004004.6(GJB2):​c.487A>C​(p.Met163Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M163V) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GJB2 NM_004004.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 O:1
• Conservation: PhyloP100: 6.20

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 Likely_pathogenic. Variant got 6 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr13-20189095-T-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GJB2	NM_004004.6	c.487A>C	p.Met163Leu	missense_variant	Exon 2 of 2	ENST00000382848.5	NP_003995.2
GJB2	XM_011535049.3	c.487A>C	p.Met163Leu	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.487A>C	p.Met163Leu	missense_variant	Exon 2 of 2	1	NM_004004.6	ENSP00000372299.4
GJB2	ENST00000382844.2	c.487A>C	p.Met163Leu	missense_variant	Exon 1 of 1	6		ENSP00000372295.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Nonsyndromic genetic hearing loss Uncertain:1

Aug 04, 2020

INGEBI, INGEBI / CONICET

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on ACMG/AMP guidelines and Hearing Loss Expert Panel (HL-EP) specific criteria: the c.487A>C, p.Met163Leu variant in GJB2 gene is absent from population databases (gnomAD, GO-ESP, 1000 genomes) meeting PM2 criteria. Computational evidence is not enough to meet neither PP3 nor BP4 rules, since REVEL score is 0.534. This variant has been detected in a family case in the proband and her affected mother. In the same report, the variant was studied in HeLa cells demonstrating that the mutant protein p.Met163Leu had defective trafficking to the plasma membrane and was associated with increased cell death (PMID:18472371). Since the functional studies performed in that report were not the specified by the HL-EP, the evidence strength has been downgraded to PS3_Supporting. Besides, the p.Met163Leu change has beed identified in heterozygous state in two hearing loss patients (PMID: 23668481;19887791) meeting PS4_Supporting rule. In summary, the clinical significance of this variant is currently uncertain (PM2, PS3_Supporting, PS4_Supporting). -

Autosomal dominant nonsyndromic hearing loss 3A Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.36
CADD	Benign	22
DANN	Benign	0.84
DEOGEN2	Uncertain	0.64	D;D;D
Eigen	Benign	-0.17
Eigen_PC	Benign	0.078
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	.;.;D
M_CAP	Benign	0.078	D
MetaRNN	Uncertain	0.67	D;D;D
MetaSVM	Uncertain	-0.041	T
MutationAssessor	Benign	1.1	L;L;L
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.2	N;N;.
REVEL	Pathogenic	0.68
Sift	Benign	0.84	T;T;.
Sift4G	Benign	1.0	T;T;.
Polyphen		0.028	B;B;B
Vest4		0.66
MutPred		0.60		Gain of sheet (P = 0.1945);Gain of sheet (P = 0.1945);Gain of sheet (P = 0.1945);
MVP		0.74
MPC		0.038
ClinPred		0.55	D
GERP RS		5.5
Varity_R		0.71
gMVP		0.86

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: rs80338949; hg19: chr13-20763234;