rs7994748

Variant names:

• chr13-20191991-G-A
• rs7994748
• NM_004004.6:c.-23+792C>T

Your query was ambiguous. Multiple possible variants found:

• chr13-20191991-G-A
• chr13-20191991-G-C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_004004.6(GJB2):​c.-23+792C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.617 in 152,110 control chromosomes in the GnomAD database, including 34,559 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.62 (34559 hom., cov: 32)
• Consequence: GJB2 NM_004004.6 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.307
• Publications: 11 publications found

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]

GJB2 Gene-Disease associations (from GenCC):

• Bart-Pumphrey syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P
• ichthyosis, hystrix-like, with hearing loss

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp
• keratoderma hereditarium mutilans

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, G2P
• palmoplantar keratoderma-deafness syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, G2P
• autosomal recessive nonsyndromic hearing loss 1A

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, G2P, PanelApp Australia
• hearing loss, autosomal recessive

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• autosomal dominant keratitis-ichthyosis-hearing loss syndrome

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Genomics England PanelApp, Ambry Genetics
• autosomal dominant nonsyndromic hearing loss 3A

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• KID syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000296095 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 13-20191991-G-A is Benign according to our data. Variant chr13-20191991-G-A is described in ClinVar as Benign. ClinVar VariationId is 1227542.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.839 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GJB2	NM_004004.6	c.-23+792C>T		intron_variant	Intron 1 of 1	ENST00000382848.5	NP_003995.2
GJB2	XM_011535049.3	c.-53C>T		5_prime_UTR_variant	Exon 1 of 2		XP_011533351.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GJB2	ENST00000382848.5	c.-23+792C>T		intron_variant	Intron 1 of 1	1	NM_004004.6	ENSP00000372299.4
ENSG00000296095	ENST00000736390.1	n.231+2464C>T		intron_variant	Intron 1 of 3

Frequencies

GnomAD3 genomes AF: 0.618 AC: 93868 AN: 151992 Hom.: 34562 Cov.: 32

Gnomad AFR AF: 0.195

Gnomad AMI AF: 0.754

Gnomad AMR AF: 0.622

Gnomad ASJ AF: 0.761

Gnomad EAS AF: 0.577

Gnomad SAS AF: 0.860

Gnomad FIN AF: 0.863

Gnomad MID AF: 0.674

Gnomad NFE AF: 0.812

Gnomad OTH AF: 0.630

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.617 AC: 93872 AN: 152110 Hom.: 34559 Cov.: 32 AF XY: 0.621 AC XY: 46181 AN XY: 74360

African (AFR) AF: 0.194 AC: 8060 AN: 41472

American (AMR) AF: 0.621 AC: 9495 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.761 AC: 2639 AN: 3470

East Asian (EAS) AF: 0.576 AC: 2967 AN: 5148

South Asian (SAS) AF: 0.861 AC: 4152 AN: 4822

European-Finnish (FIN) AF: 0.863 AC: 9140 AN: 10596

Middle Eastern (MID) AF: 0.667 AC: 196 AN: 294

European-Non Finnish (NFE) AF: 0.812 AC: 55197 AN: 68002

Other (OTH) AF: 0.634 AC: 1338 AN: 2112

Alfa AF: 0.698 Hom.: 7696

Bravo AF: 0.573

Asia WGS AF: 0.715 AC: 2488 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jan 18, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 27827000, 26075227) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	6.5
DANN	Benign	0.80
PhyloP100		0.31
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs7994748; hg19: chr13-20766130;