rs3751385

Variant names:

• chr13-20188817-A-G
• rs3751385
• NM_004004.6:c.*84T>C

Your query was ambiguous. Multiple possible variants found:

• chr13-20188817-A-G
• chr13-20188817-A-C
• chr13-20188817-A-T

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.*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:9
• Conservation: PhyloP100: 2.22
• Publications: 56 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=-0.82).
• BP6: Variant 13-20188817-A-G is Benign according to our data. Variant chr13-20188817-A-G is described in ClinVar as Benign. ClinVar VariationId 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.

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.*84T>C		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.*84T>C		3_prime_UTR	Exon 2 of 2	ENSP00000372299.4	P29033
	GJB2	ENST00000382844.2	TSL:6	c.*84T>C		3_prime_UTR	Exon 1 of 1	ENSP00000372295.1	P29033
	GJB2	ENST00000906230.1		c.*84T>C		3_prime_UTR	Exon 2 of 2	ENSP00000576289.1

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

African (AFR) AF: 0.586 AC: 13588 AN: 23178

American (AMR) AF: 0.667 AC: 28717 AN: 43086

Ashkenazi Jewish (ASJ) AF: 0.815 AC: 18547 AN: 22766

East Asian (EAS) AF: 0.564 AC: 20800 AN: 36904

South Asian (SAS) AF: 0.868 AC: 64680 AN: 74554

European-Finnish (FIN) AF: 0.870 AC: 41737 AN: 47954

Middle Eastern (MID) AF: 0.776 AC: 3668 AN: 4724

European-Non Finnish (NFE) AF: 0.827 AC: 520090 AN: 628626

Other (OTH) AF: 0.794 AC: 33858 AN: 42650

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

African (AFR) AF: 0.588 AC: 24399 AN: 41490

American (AMR) AF: 0.679 AC: 10381 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.809 AC: 2807 AN: 3470

East Asian (EAS) AF: 0.578 AC: 2980 AN: 5160

South Asian (SAS) AF: 0.867 AC: 4185 AN: 4826

European-Finnish (FIN) AF: 0.875 AC: 9276 AN: 10600

Middle Eastern (MID) AF: 0.772 AC: 227 AN: 294

European-Non Finnish (NFE) AF: 0.824 AC: 56028 AN: 68002

Other (OTH) AF: 0.733 AC: 1551 AN: 2116

Alfa AF: 0.793 Hom.: 81542

Bravo AF: 0.714

Asia WGS AF: 0.751 AC: 2612 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	15
DANN	Benign	0.67
PhyloP100		2.2
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: rs3751385; hg19: chr13-20762956; COSMIC: COSV67010734;