rs1273330603

chr13-20189094-A-Cchr13-20189094-A-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Strong

The NM_004004.6(GJB2):c.488T>G(p.Met163Arg) 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 Uncertain significance (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M163T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GJB2 NM_004004.6 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U: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 hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 7 uncertain 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 ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 21388.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=9, Likely_pathogenic=2, not_provided=1}.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.974

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GJB2	NM_004004.6	c.488T>G	p.Met163Arg	missense_variant	2/2	ENST00000382848.5
GJB2	XM_011535049.3	c.488T>G	p.Met163Arg	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GJB2	ENST00000382848.5	c.488T>G	p.Met163Arg	missense_variant	2/2	1	NM_004004.6	P1
GJB2	ENST00000382844.2	c.488T>G	p.Met163Arg	missense_variant	1/1			P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: no assertion criteria provided

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
Cadd	Uncertain	25
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.91	D;D;D
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.97	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.5	M;M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-4.9	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		0.94
MutPred		0.79		Gain of catalytic residue at M163 (P = 0.0216);Gain of catalytic residue at M163 (P = 0.0216);Gain of catalytic residue at M163 (P = 0.0216);
MVP		0.95
MPC		0.28
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.98
gMVP		0.98

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr13-20763233;