chr13-20187749-C-T

Variant names:

• chr13-20187749-C-T
• rs7623
• NM_004004.6:c.*1152G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004004.6(GJB2):​c.*1152G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.902 in 152,246 control chromosomes in the GnomAD database, including 62,625 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.90 (62625 hom., cov: 32)
  • Failed GnomAD Quality Control
• Consequence: GJB2 NM_004004.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.115
• Publications: 13 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: G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• 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, G2P, Genomics England PanelApp
• palmoplantar keratoderma-deafness syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, G2P
• syndromic genetic hearing loss

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• autosomal recessive nonsyndromic hearing loss 1A

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
• nonsyndromic genetic hearing loss

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

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

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

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000296095 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.99).
• BP6: Variant 13-20187749-C-T is Benign according to our data. Variant chr13-20187749-C-T is described in ClinVar as Benign. ClinVar VariationId is 311356.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.977 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004004.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GJB2	NM_004004.6	MANE Select	c.*1152G>A		3_prime_UTR	Exon 2 of 2	NP_003995.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GJB2	ENST00000382848.5	TSL:1 MANE Select	c.*1152G>A		3_prime_UTR	Exon 2 of 2	ENSP00000372299.4	P29033
	GJB2	ENST00000382844.2	TSL:6	c.*1152G>A		3_prime_UTR	Exon 1 of 1	ENSP00000372295.1	P29033
	GJB2	ENST00000906230.1		c.*1152G>A		3_prime_UTR	Exon 2 of 2	ENSP00000576289.1

Frequencies

GnomAD3 genomes AF: 0.902 AC: 137151 AN: 152128 Hom.: 62580 Cov.: 32

Gnomad AFR AF: 0.746

Gnomad AMI AF: 0.923

Gnomad AMR AF: 0.936

Gnomad ASJ AF: 0.932

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.967

Gnomad FIN AF: 0.963

Gnomad MID AF: 0.959

Gnomad NFE AF: 0.964

Gnomad OTH AF: 0.914

GnomAD4 exome Data not reliable, filtered out with message: AC0 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

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) AC: 0 AN: 0

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.902 AC: 137253 AN: 152246 Hom.: 62625 Cov.: 32 AF XY: 0.903 AC XY: 67224 AN XY: 74442

African (AFR) AF: 0.746 AC: 30963 AN: 41490

American (AMR) AF: 0.937 AC: 14325 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.932 AC: 3235 AN: 3472

East Asian (EAS) AF: 0.999 AC: 5182 AN: 5186

South Asian (SAS) AF: 0.967 AC: 4670 AN: 4828

European-Finnish (FIN) AF: 0.963 AC: 10226 AN: 10614

Middle Eastern (MID) AF: 0.952 AC: 280 AN: 294

European-Non Finnish (NFE) AF: 0.964 AC: 65596 AN: 68040

Other (OTH) AF: 0.915 AC: 1936 AN: 2116

Alfa AF: 0.937 Hom.: 23248

Bravo AF: 0.893

Asia WGS AF: 0.975 AC: 3390 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Autosomal dominant nonsyndromic hearing loss 3A (1)
-	-	1	Autosomal recessive nonsyndromic hearing loss 1A (1)
-	-	1	Ichthyosis, hystrix-like, with hearing loss (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	0.89
DANN	Benign	0.28
PhyloP100		-0.12
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: rs7623; hg19: chr13-20761888;