rs55704559

Variant names:

• chr13-20188733-T-C
• rs55704559
• NM_004004.6:c.*168A>G

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.*168A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0463 in 636,298 control chromosomes in the GnomAD database, including 851 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.040 (173 hom., cov: 33)
  • Exomes 𝑓: 0.048 (678 hom.)
• Consequence: GJB2 NM_004004.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.65
• Publications: 3 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=-0.85).
• BP6: Variant 13-20188733-T-C is Benign according to our data. Variant chr13-20188733-T-C is described in ClinVar as Benign. ClinVar VariationId is 311369.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.059 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.*168A>G		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.*168A>G		3_prime_UTR	Exon 2 of 2	ENSP00000372299.4	P29033
	GJB2	ENST00000382844.2	TSL:6	c.*168A>G		3_prime_UTR	Exon 1 of 1	ENSP00000372295.1	P29033
	GJB2	ENST00000906230.1		c.*168A>G		3_prime_UTR	Exon 2 of 2	ENSP00000576289.1

Frequencies

GnomAD3 genomes AF: 0.0400 AC: 6095 AN: 152232 Hom.: 173 Cov.: 33

Gnomad AFR AF: 0.0108

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.0473

Gnomad ASJ AF: 0.0352

Gnomad EAS AF: 0.00519

Gnomad SAS AF: 0.0250

Gnomad FIN AF: 0.0387

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0605

Gnomad OTH AF: 0.0497

GnomAD4 exome AF: 0.0483 AC: 23397 AN: 483948 Hom.: 678 Cov.: 4 AF XY: 0.0472 AC XY: 12168 AN XY: 257894

African (AFR) AF: 0.0103 AC: 139 AN: 13440

American (AMR) AF: 0.0383 AC: 946 AN: 24688

Ashkenazi Jewish (ASJ) AF: 0.0373 AC: 574 AN: 15386

East Asian (EAS) AF: 0.00744 AC: 235 AN: 31576

South Asian (SAS) AF: 0.0254 AC: 1246 AN: 49140

European-Finnish (FIN) AF: 0.0423 AC: 1309 AN: 30916

Middle Eastern (MID) AF: 0.0540 AC: 129 AN: 2388

European-Non Finnish (NFE) AF: 0.0605 AC: 17466 AN: 288860

Other (OTH) AF: 0.0491 AC: 1353 AN: 27554

GnomAD4 genome AF: 0.0400 AC: 6094 AN: 152350 Hom.: 173 Cov.: 33 AF XY: 0.0385 AC XY: 2869 AN XY: 74508

African (AFR) AF: 0.0108 AC: 448 AN: 41584

American (AMR) AF: 0.0472 AC: 722 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0352 AC: 122 AN: 3468

East Asian (EAS) AF: 0.00520 AC: 27 AN: 5190

South Asian (SAS) AF: 0.0251 AC: 121 AN: 4828

European-Finnish (FIN) AF: 0.0387 AC: 411 AN: 10626

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.0605 AC: 4118 AN: 68026

Other (OTH) AF: 0.0497 AC: 105 AN: 2114

Alfa AF: 0.0493 Hom.: 94

Bravo AF: 0.0390

Asia WGS AF: 0.0150 AC: 51 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.041
DANN	Benign	0.51
PhyloP100		-1.7
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: rs55704559; hg19: chr13-20762872;