rs1555341986

Variant names:

• chr13-20189425-A-G
• rs1555341986
• NM_004004.6:c.157T>C

Your query was ambiguous. Multiple possible variants found:

• chr13-20189425-A-G
• chr13-20189425-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PP3_Strong

The NM_004004.6(GJB2):​c.157T>C​(p.Cys53Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,460,150 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: GJB2 NM_004004.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.26

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
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.996

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GJB2	NM_004004.6	c.157T>C	p.Cys53Arg	missense_variant	Exon 2 of 2	ENST00000382848.5	NP_003995.2
GJB2	XM_011535049.3	c.157T>C	p.Cys53Arg	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.157T>C	p.Cys53Arg	missense_variant	Exon 2 of 2	1	NM_004004.6	ENSP00000372299.4
GJB2	ENST00000382844.2	c.157T>C	p.Cys53Arg	missense_variant	Exon 1 of 1	6		ENSP00000372295.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1460150 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 725996

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 1A Uncertain:1

Jun 09, 2017

Counsyl

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.60
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D;D;D
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	.;.;D
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	1.0	D;D;D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Pathogenic	3.7	H;H;H
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-12	D;D;.
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;D;.
Sift4G	Pathogenic	0.0	D;D;.
Polyphen		1.0	D;D;D
Vest4		0.99
MutPred		0.97		Gain of catalytic residue at C53 (P = 0.0446);Gain of catalytic residue at C53 (P = 0.0446);Gain of catalytic residue at C53 (P = 0.0446);
MVP		0.95
MPC		0.35
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.99
gMVP		0.99

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: rs1555341986; hg19: chr13-20763564;