rs111033296

Positions:

• chr13-20189463-G-C
• chr13-20189463-G-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_004004.6(GJB2):​c.119C>G​(p.Ala40Gly) 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A40E) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GJB2 NM_004004.6 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.94

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 12 ACMG points.

• PM1: In a transmembrane_region Helical (size 19) in uniprot entity CXB2_HUMAN there are 13 pathogenic changes around while only 1 benign (93%) 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 chr13-20189463-G-T is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant 13-20189463-G-C is Pathogenic according to our data. Variant chr13-20189463-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 188925.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr13-20189463-G-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GJB2	NM_004004.6	c.119C>G	p.Ala40Gly	missense_variant	2/2	ENST00000382848.5	NP_003995.2
GJB2	XM_011535049.3	c.119C>G	p.Ala40Gly	missense_variant	2/2		XP_011533351.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GJB2	ENST00000382848.5	c.119C>G	p.Ala40Gly	missense_variant	2/2	1	NM_004004.6	ENSP00000372299.4
GJB2	ENST00000382844.2	c.119C>G	p.Ala40Gly	missense_variant	1/1	6		ENSP00000372295.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 1A Pathogenic:1

Likely pathogenic, criteria provided, single submitter

literature only

Counsyl

Aug 20, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.40
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	D;D;D
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.83	.;.;T
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.8	L;L;L
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-3.9	D;D;.
REVEL	Pathogenic	0.77
Sift	Benign	0.041	D;D;.
Sift4G	Benign	0.072	T;T;.
Polyphen		0.73	P;P;P
Vest4		0.80
MutPred		0.95		Loss of stability (P = 0.0412);Loss of stability (P = 0.0412);Loss of stability (P = 0.0412);
MVP		0.98
MPC		0.21
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.79
gMVP		0.91

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: rs111033296; hg19: chr13-20763602;