rs3751385

Positions:

• chr13-20188817-A-G

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.*84T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.797 in 1,076,606 control chromosomes in the GnomAD database, including 346,143 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.74 (42626 hom., cov: 33)
  • Exomes 𝑓: 0.81 (303517 hom.)
• Consequence: GJB2 NM_004004.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 2.22

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=-0.82).
• BP6: Variant 13-20188817-A-G is Benign according to our data. Variant chr13-20188817-A-G is described in ClinVar as [Benign]. Clinvar id is 36277.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.845 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GJB2	NM_004004.6	c.*84T>C		3_prime_UTR_variant	2/2	ENST00000382848.5
GJB2	XM_011535049.3	c.*84T>C		3_prime_UTR_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GJB2	ENST00000382848.5	c.*84T>C		3_prime_UTR_variant	2/2	1	NM_004004.6	P1
GJB2	ENST00000382844.2	c.*84T>C		3_prime_UTR_variant	1/1			P1

Frequencies

GnomAD3 genomes AF: 0.740 AC: 112527 AN: 152046 Hom.: 42608 Cov.: 33

Gnomad AFR AF: 0.588

Gnomad AMI AF: 0.843

Gnomad AMR AF: 0.679

Gnomad ASJ AF: 0.809

Gnomad EAS AF: 0.578

Gnomad SAS AF: 0.866

Gnomad FIN AF: 0.875

Gnomad MID AF: 0.775

Gnomad NFE AF: 0.824

Gnomad OTH AF: 0.731

GnomAD4 exome AF: 0.807 AC: 745685 AN: 924442 Hom.: 303517 Cov.: 12 AF XY: 0.811 AC XY: 390752 AN XY: 481938

Gnomad4 AFR exome AF: 0.586

Gnomad4 AMR exome AF: 0.667

Gnomad4 ASJ exome AF: 0.815

Gnomad4 EAS exome AF: 0.564

Gnomad4 SAS exome AF: 0.868

Gnomad4 FIN exome AF: 0.870

Gnomad4 NFE exome AF: 0.827

Gnomad4 OTH exome AF: 0.794

GnomAD4 genome AF: 0.740 AC: 112601 AN: 152164 Hom.: 42626 Cov.: 33 AF XY: 0.738 AC XY: 54930 AN XY: 74400

Gnomad4 AFR AF: 0.588

Gnomad4 AMR AF: 0.679

Gnomad4 ASJ AF: 0.809

Gnomad4 EAS AF: 0.578

Gnomad4 SAS AF: 0.867

Gnomad4 FIN AF: 0.875

Gnomad4 NFE AF: 0.824

Gnomad4 OTH AF: 0.733

Alfa AF: 0.802 Hom.: 65421

Bravo AF: 0.714

Asia WGS AF: 0.751 AC: 2612 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 1A Benign:3

Benign, criteria provided, single submitter	clinical testing	Pars Genome Lab	Jul 01, 2021	- -
Benign, criteria provided, single submitter	curation	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 18, 2011	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 29318123) -

Autosomal dominant nonsyndromic hearing loss 3A 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	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	15
DANN	Benign	0.67

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: rs3751385; hg19: chr13-20762956; COSMIC: COSV67010734;