13-20189167-T-A

Position:

• chr13-20189167-T-A

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP3_Moderate PP5

The NM_004004.6(GJB2):​c.415A>T​(p.Ser139Cys) 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S139N) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GJB2 NM_004004.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 7.97

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 9 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 chr13-20189166-C-T is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.935
• PP5: Variant 13-20189167-T-A is Pathogenic according to our data. Variant chr13-20189167-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 553209.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GJB2	NM_004004.6	c.415A>T	p.Ser139Cys	missense_variant	2/2	ENST00000382848.5	NP_003995.2
GJB2	XM_011535049.3	c.415A>T	p.Ser139Cys	missense_variant	2/2		XP_011533351.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GJB2	ENST00000382848.5	c.415A>T	p.Ser139Cys	missense_variant	2/2	1	NM_004004.6	ENSP00000372299	P1
GJB2	ENST00000382844.2	c.415A>T	p.Ser139Cys	missense_variant	1/1			ENSP00000372295	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 19, 2023

This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 139 of the GJB2 protein (p.Ser139Cys). 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. This variant disrupts the p.Ser139 amino acid residue in GJB2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11493200, 12172394, 16380907, 16864573, 17041943, 21465647, 27785406). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 553209). This missense change has been observed in individual(s) with deafness (PMID: 23751281). This variant is not present in population databases (gnomAD no frequency). -

Autosomal recessive nonsyndromic hearing loss 1A Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

Aug 07, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.90	D;D;D
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.94	.;.;D
M_CAP	Pathogenic	0.73	D
MetaRNN	Pathogenic	0.94	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.9	M;M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-4.6	D;D;.
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0010	D;D;.
Sift4G	Uncertain	0.0030	D;D;.
Polyphen		1.0	D;D;D
Vest4		0.79
MutPred		0.65		Loss of MoRF binding (P = 0.0903);Loss of MoRF binding (P = 0.0903);Loss of MoRF binding (P = 0.0903);
MVP		0.98
MPC		0.28
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.92
gMVP		0.93

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: rs1555341907; hg19: chr13-20763306;