chr13-20189571-C-T

Position:

• chr13-20189571-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM1 BP4_Strong BP6 BS2_Supporting

The ENST00000382848.5(GJB2):​c.11G>A​(p.Gly4Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000231 in 1,614,044 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00055 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00020 (7 hom.)
• Consequence: GJB2 ENST00000382848.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:15
• Conservation: PhyloP100: 0.410

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]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in ENST00000382848.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.01572612).
• BP6: Variant 13-20189571-C-T is Benign according to our data. Variant chr13-20189571-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 44724.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=2, Likely_benign=10}. Variant chr13-20189571-C-T is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAdExome4 at 7 AD,AR,Digenic geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GJB2	NM_004004.6	c.11G>A	p.Gly4Asp	missense_variant	2/2	ENST00000382848.5	NP_003995.2
GJB2	XM_011535049.3	c.11G>A	p.Gly4Asp	missense_variant	2/2		XP_011533351.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GJB2	ENST00000382848.5	c.11G>A	p.Gly4Asp	missense_variant	2/2	1	NM_004004.6	ENSP00000372299	P1
GJB2	ENST00000382844.2	c.11G>A	p.Gly4Asp	missense_variant	1/1			ENSP00000372295	P1

Frequencies

GnomAD3 genomes AF: 0.000552 AC: 84 AN: 152148 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00140

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00366

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000437 AC: 109 AN: 249290 Hom.: 1 AF XY: 0.000422 AC XY: 57 AN XY: 134958

Gnomad AFR exome AF: 0.00148

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00391

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000896

Gnomad OTH exome AF: 0.000816

GnomAD4 exome AF: 0.000198 AC: 289 AN: 1461778 Hom.: 7 Cov.: 32 AF XY: 0.000183 AC XY: 133 AN XY: 727194

Gnomad4 AFR exome AF: 0.000508

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00194

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000809

Gnomad4 OTH exome AF: 0.00285

GnomAD4 genome AF: 0.000552 AC: 84 AN: 152266 Hom.: 1 Cov.: 33 AF XY: 0.000524 AC XY: 39 AN XY: 74446

Gnomad4 AFR AF: 0.00140

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00367

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000388 Hom.: 2

Bravo AF: 0.000661

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000420 AC: 51

Asia WGS AF: 0.00808 AC: 28 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:15

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:8

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 27, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2020	This variant is associated with the following publications: (PMID: 12792423, 19043807, 22613756, 21122151, 25388846, 17426645, 26043044, 20593197, 23638949, 25087612, 15070423, 27153395, 19366456, 17041943, 24612839, 21162657, 15967879, 17666888, 24341454, 19929407, 19235794, 19877196, 21287563, 15832357, 30245029, 31992338) -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 28, 2018	The GJB2 c.11G>A, p.Gly4Asp variant (rs111033222) has been reported in individuals with non-syndromic hearing impairment (Dai 2009, Hwa 2003, Tang 2006, Yao 2013). However, it has also been reported in the general population at similar frequencies (Roux 2004, Snoeckx 2005, Tang 2006, Zainal 2012), and found in-cis with a pathogenic variant (Yuan 2010). The variant is listed in ClinVar (Variation ID: 44724), and observed in the Genome Aggregation Database at a frequency of 0.046% (126/275028 alleles, including 1 homozygote). The glycine at residue 4 is highly conserved, but computational algorithms (PolyPhen-2, SIFT) predict that the variant has no impact on the protein. Based on the above information, the variant is considered likely benign. References: Dai P et al. GJB2 mutation spectrum in 2,063 Chinese patients with nonsyndromic hearing impairment. J Transl Med. 2009; 7:26. Hwa H et al. Mutation spectrum of the connexin 26 (GJB2) gene in Taiwanese patients with prelingual deafness. Genet Med. 2003; 5(3):161-5. Roux A et al. Molecular epidemiology of DFNB1 deafness in France. BMC Med Genet. 2004; 5:5. Snoeckx R et al. GJB2 (connexin 26) mutations are not a major cause of hearing loss in the Indonesian population. Am J Med Genet A. 2005; 135(2):126-9. Tang H et al. DNA sequence analysis of GJB2, encoding connexin 26: observations from a population of hearing impaired cases and variable carrier rates, complex genotypes, and ethnic stratification of alleles among controls. Am J Med Genet A. 2006; 140(22):2401-15. Yao G et al. Novel mutations of SLC26A4 in Chinese patients with nonsyndromic hearing loss. Acta Otolaryngol. 2013; 133(8):833-41. Yuan Y et al. Prevalence of the GJB2 IVS1+1G >A mutation in Chinese hearing loss patients with monoallelic pathogenic mutation in the coding region of GJB2. J Transl Med. 2010;8:127. Zainal S et al. Mutation detection in GJB2 gene among Malays with non-syndromic hearing loss. Int J Pediatr Otorhinolaryngol. 2012; 76(8):1175-9. -

not specified Uncertain:1 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 30, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 28, 2011	Gly4Asp in exon 2 of GJB2: This variant is not expected to have clinical signifi cance due to an equal occurrence in probands (0.52% (25/4779)) and controls (0.3 5% (23/665)) (Yaun 2010, Dia 2009, Han 2008, Lee 2008, Tang 2006, Snoeckx 2005, Roux 2004, Hwa 2003) with a 10% (20/200) frequency in the Indonesian population (Snoeckx 2005). In addition, this variant has been identified in one individual in cis with another pathogenic GJB2 variant (Yaun 2010). -
Uncertain significance, flagged submission	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 16, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 10, 2022	Variant summary: GJB2 c.11G>A (p.Gly4Asp) results in a non-conservative amino acid change located in the Connexin, N-terminal domain (IPR013092) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00054 in 262830 control chromosomes, predominantly at a frequency of 0.0039 within the East Asian subpopulation in the gnomAD database, and in publication data (Hwa 2003, Roux 2004, Han 2008, Chiong 2013, Snoeckx 2005, Zainal 2012). Though this frequency is not significantly higher than estimated for a pathogenic variant in GJB2 causing Autosomal Recessive Non-Syndromic Hearing Loss (0.00054 vs 0.025), at least 2 homozygous occurrences were observed among healthy controls (gnomAD and Snoeckx 2005), suggesting against the pathogenic role for the variant. Though the c.11G>A variant has been reported in the literature in multiple individuals affected with Autosomal Recessive Non-Syndromic Hearing Loss, who were compound heterozygous for this variant and another pathogenic variant, viz. p.V37I (Al-Qahtani 2010, Dai 2009, Lipan 2011) and c.235delC (Xin 2013), in one patient this variant also co-occurred in cis with a pathogenic variant, IVS1+1G>A, suggesting against pathogenicity (Yuan 2010). In addition, in two studies (carried out in East Asian subpopulations), the variant was observed in a similar (or even larger) frequency in healthy controls than in patients (Snoeckx 2005, Zainal 2012). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine ClinVar submitters (evaluation after 2014) cite the variant with a predominant consensus as likely benign (n=8) (VUS, n=1). Based on the evidence outlined above, the variant was classified as likely benign. -

Autosomal recessive nonsyndromic hearing loss 1A Uncertain:1 Benign:2

Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Apr 03, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Mar 31, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3C. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with both deafness and skin conditions (OMIM). Dominant negative is also a suggested mechanism (PMID: 28428247). (I) 0108 - This gene is associated with both recessive and dominant disease. Autosomal dominant disease is commonly associated with pathogenic protein truncating and missense variants whereas autosomal recessive disease is commonly associated with bi-allelic loss-of-function variants (NIH Genetics Home Reference, PMID: 12792423). (I) 0112 - The condition associated with this gene has incomplete penetrance (PMID:31160754). (I) 0115 - Variants in this gene are known to have variable expressivity. Inter- and intra-familial variability have been reported with disease severity ranging from mild to profound. Truncating variants are commonly associated with more severe hearing loss (GeneReviews). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to aspartic acid. (I) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (128 heterozygotes, 1 homozygote). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (p.(Gly4Val): 4 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions, low conservation and moderate amino acid change. (I) 0600 - Variant is located in the annotated connexin domain (DECIPHER). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been classified as likely benign and VUS in the literature and by multiple clinical diagnostic laboratories, primarily due to its allele frequency in the general population (PMIDs: 15070423, 17041943, 21287563, 30245029, ClinVar). However, this variant has also been observed in affected individuals either as heterozygous or compound heterozygous and classified as pathogenic (PMIDs: 12792423, 31992338). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Ichthyosis, hystrix-like, with hearing loss Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Autosomal dominant nonsyndromic hearing loss 3A Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	16
DANN	Benign	0.93
DEOGEN2	Uncertain	0.71	D;D;D
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.55	D
LIST_S2	Benign	0.78	.;.;T
M_CAP	Benign	0.084	D
MetaRNN	Benign	0.016	T;T;T
MetaSVM	Uncertain	0.69	D
MutationAssessor	Benign	1.4	L;L;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-2.1	N;N;.
REVEL	Uncertain	0.36
Sift	Benign	0.059	T;T;.
Sift4G	Benign	0.27	T;T;.
Polyphen		0.088	B;B;B
Vest4		0.15
MVP		0.85
MPC		0.046
ClinPred		0.012	T
GERP RS		4.5
Varity_R		0.42
gMVP		0.92

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

Publications

LitVar

Other links and lift over

dbSNP: rs111033222; hg19: chr13-20763710;