rs55704559

Positions:

• chr13-20188733-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004004.6(GJB2):​c.*168A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0463 in 636,298 control chromosomes in the GnomAD database, including 851 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.040 (173 hom., cov: 33)
  • Exomes 𝑓: 0.048 (678 hom.)
• Consequence: GJB2 NM_004004.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.65

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 13-20188733-T-C is Benign according to our data. Variant chr13-20188733-T-C is described in ClinVar as [Benign]. Clinvar id is 311369.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.059 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GJB2	NM_004004.6	c.*168A>G		3_prime_UTR_variant	2/2	ENST00000382848.5	NP_003995.2
GJB2	XM_011535049.3	c.*168A>G		3_prime_UTR_variant	2/2		XP_011533351.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GJB2	ENST00000382848.5	c.*168A>G		3_prime_UTR_variant	2/2	1	NM_004004.6	ENSP00000372299	P1
GJB2	ENST00000382844.2	c.*168A>G		3_prime_UTR_variant	1/1			ENSP00000372295	P1

Frequencies

GnomAD3 genomes AF: 0.0400 AC: 6095 AN: 152232 Hom.: 173 Cov.: 33

Gnomad AFR AF: 0.0108

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.0473

Gnomad ASJ AF: 0.0352

Gnomad EAS AF: 0.00519

Gnomad SAS AF: 0.0250

Gnomad FIN AF: 0.0387

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0605

Gnomad OTH AF: 0.0497

GnomAD4 exome AF: 0.0483 AC: 23397 AN: 483948 Hom.: 678 Cov.: 4 AF XY: 0.0472 AC XY: 12168 AN XY: 257894

Gnomad4 AFR exome AF: 0.0103

Gnomad4 AMR exome AF: 0.0383

Gnomad4 ASJ exome AF: 0.0373

Gnomad4 EAS exome AF: 0.00744

Gnomad4 SAS exome AF: 0.0254

Gnomad4 FIN exome AF: 0.0423

Gnomad4 NFE exome AF: 0.0605

Gnomad4 OTH exome AF: 0.0491

GnomAD4 genome AF: 0.0400 AC: 6094 AN: 152350 Hom.: 173 Cov.: 33 AF XY: 0.0385 AC XY: 2869 AN XY: 74508

Gnomad4 AFR AF: 0.0108

Gnomad4 AMR AF: 0.0472

Gnomad4 ASJ AF: 0.0352

Gnomad4 EAS AF: 0.00520

Gnomad4 SAS AF: 0.0251

Gnomad4 FIN AF: 0.0387

Gnomad4 NFE AF: 0.0605

Gnomad4 OTH AF: 0.0497

Alfa AF: 0.0523 Hom.: 58

Bravo AF: 0.0390

Asia WGS AF: 0.0150 AC: 51 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 1A Benign:2

Benign, criteria provided, single submitter	clinical testing	Pars Genome Lab	Jul 01, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 22, 2018	- -

Autosomal dominant nonsyndromic hearing loss 3A Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Pars Genome Lab	Jul 01, 2021	- -

Ichthyosis, hystrix-like, with hearing loss Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.041
DANN	Benign	0.51

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: rs55704559; hg19: chr13-20762872;