ENST00000736390.1:n.231+1326A>G

Variant names:

• chr13-20193129-T-C
• rs9552101
• ENST00000736390.1:n.231+1326A>G

Variant summary

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

The ENST00000736390.1(ENSG00000296095):​n.231+1326A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.804 in 144,002 control chromosomes in the GnomAD database, including 50,782 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.80 (50766 hom., cov: 21)
  • Exomes 𝑓: 0.92 (16 hom.)
• Consequence: ENSG00000296095 ENST00000736390.1 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.63
• Publications: 6 publications found

Genes affected

ENSG00000296095 (HGNC:):

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 13-20193129-T-C is Benign according to our data. Variant chr13-20193129-T-C is described in ClinVar as Benign. ClinVar VariationId is 1242260.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.975 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000736390.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GJB2	NM_004004.6	MANE Select	c.-369A>G		upstream_gene	N/A	NP_003995.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENSG00000296095	ENST00000736390.1		n.231+1326A>G		intron	N/A
	GJB2	ENST00000382848.5	TSL:1 MANE Select	c.-369A>G		upstream_gene	N/A	ENSP00000372299.4

Frequencies

GnomAD3 genomes AF: 0.804 AC: 115774 AN: 143910 Hom.: 50769 Cov.: 21

Gnomad AFR AF: 0.382

Gnomad AMI AF: 0.835

Gnomad AMR AF: 0.884

Gnomad ASJ AF: 0.891

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.966

Gnomad FIN AF: 0.963

Gnomad MID AF: 0.895

Gnomad NFE AF: 0.959

Gnomad OTH AF: 0.830

GnomAD4 exome AF: 0.917 AC: 33 AN: 36 Hom.: 16 AF XY: 0.923 AC XY: 24 AN XY: 26

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 1.00 AC: 2 AN: 2

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.969 AC: 31 AN: 32

Other (OTH) AF: 0.00 AC: 0 AN: 2

GnomAD4 genome AF: 0.804 AC: 115787 AN: 143966 Hom.: 50766 Cov.: 21 AF XY: 0.809 AC XY: 56941 AN XY: 70406

African (AFR) AF: 0.382 AC: 13781 AN: 36096

American (AMR) AF: 0.884 AC: 13182 AN: 14904

Ashkenazi Jewish (ASJ) AF: 0.891 AC: 3068 AN: 3442

East Asian (EAS) AF: 0.999 AC: 4756 AN: 4760

South Asian (SAS) AF: 0.967 AC: 4506 AN: 4662

European-Finnish (FIN) AF: 0.963 AC: 9726 AN: 10100

Middle Eastern (MID) AF: 0.887 AC: 259 AN: 292

European-Non Finnish (NFE) AF: 0.959 AC: 64099 AN: 66816

Other (OTH) AF: 0.832 AC: 1680 AN: 2020

Alfa AF: 0.856 Hom.: 6897

Bravo AF: 0.753

Asia WGS AF: 0.938 AC: 3247 AN: 3462

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	4.7
DANN	Benign	0.45
PhyloP100		-1.6
PromoterAI		0.020	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs9552101; hg19: chr13-20767268;