rs111033188

chr13-20189214-G-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PM1 BP4_Strong BP6_Very_Strong

The NM_004004.6(GJB2):c.368C>A(p.Thr123Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000193 in 1,613,774 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00019 (0 hom.)
• Consequence: GJB2 NM_004004.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -2.45

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 Benign. Variant got -10 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 6 uncertain in NM_004004.6
• BP4: Computational evidence support a benign effect (MetaRNN=0.013856769).
• BP6: Variant 13-20189214-G-T is Benign according to our data. Variant chr13-20189214-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 44743.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GJB2	NM_004004.6	c.368C>A	p.Thr123Asn	missense_variant	2/2	ENST00000382848.5
GJB2	XM_011535049.3	c.368C>A	p.Thr123Asn	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GJB2	ENST00000382848.5	c.368C>A	p.Thr123Asn	missense_variant	2/2	1	NM_004004.6	P1
GJB2	ENST00000382844.2	c.368C>A	p.Thr123Asn	missense_variant	1/1			P1

Frequencies

GnomAD3 genomes AF: 0.000210 AC: 32 AN: 152212 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00559

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000508 AC: 127 AN: 250204 Hom.: 1 AF XY: 0.000465 AC XY: 63 AN XY: 135386

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00653

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000442

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000192 AC: 281 AN: 1461444 Hom.: 0 Cov.: 33 AF XY: 0.000193 AC XY: 140 AN XY: 727046

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00622

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000189

Gnomad4 OTH exome AF: 0.000149

GnomAD4 genome AF: 0.000204 AC: 31 AN: 152330 Hom.: 0 Cov.: 33 AF XY: 0.000242 AC XY: 18 AN XY: 74494

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00541

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000527 Hom.: 0

Bravo AF: 0.000283

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000544 AC: 66

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 06, 2019	Variant summary: GJB2 c.368C>A (p.Thr123Asn) results in a non-conservative amino acid change located in the central part of the cytoplasmic loop (CL) domain (Locke 2009) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. One study indicates potential phosphorylation at this residue, however the functional significance of this post-translational modification is unknown (Locke 2009). The variant allele was found at a frequency of 0.00059 in 255584 control chromosomes, predominantly observed in the East Asian subpopulation at a frequency of 0.0065 in the gnomAD database, including 1 homozygote. This frequency is lower than the estimated maximal expected allele frequency of a pathogenic GJB2 variant (0.025) (when considering autosomal recessive inheritance). However, in certain East Asian subpopulations even higher occurrences were reported e.g. in Koreans it was found at a frequency of 0.01 (gnomAD 2.1); that suggests the variant is likely a benign polymorphism found primarily in the populations of East Asian origin. This variant has been reported in multiple nonsyndromic sensorineural hearing loss (NSHL) patients (mainly East Asian ethnicity) without strong evidence for causality. The high occurrence in controls and the co-occurrence of other GJB2 disease variants in at least 2 patients argue against a potential dominant inheritance pattern (Dai 2009, Wu 2016). Many studies have reported the variant in patients with comparable frequencies (or lower than) detected in controls (e.g. Dai 2009, Nishio 2017), supporting the benign nature of this variant. A co-occurrence with a pathogenic variant (c.235delC) in trans was reported in a normal-hearing carrier (He 2017); further supporting a benign role for the variant. Though some studies raised the possibility that this variant can contribute to multigenic disorders, postulating that a combination of this variant with heterozygous alterations in other genes may be implicated in deafness (Chow 2017, Wu 2016), they provided no convincing evidence for the causative relationship. Two other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and both of these laboratories classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as benign. -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 10, 2016	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 09, 2011	Thr123Asn in exon 2 of GJB2: This variant has been previously reported in patien ts with hearing loss as well as in control subjects as a rare polymorphism (Park 2000, Tang 2006, Cryns 2004, Dai 2009, Hwa 2003, Oguchi 2005, Ohtsuka 2003, Shi 2004, Snoeckx 2005). The allele frequencies of this variant are higher in the c ontrol group (~0.9%) than in the patient group (~0.4%), suggesting that this var iant does not have clinical significance. -

Autosomal recessive nonsyndromic hearing loss 1A 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 27, 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. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 22, 2020	This variant is associated with the following publications: (PMID: 15504600, 19043807, 12792423, 15700112, 16380907, 12172394, 22613756, 12560944, 20497192, 31992338, 28900111, 19715472, 30245029, 25262649, 25266519, 10983956, 20607074, 19366456, 14985372, 23638949, 23826813, 17041943, 25388846, 22384008, 22695344, 25493717, 17666888, 20593197, 21162657) -

Autosomal dominant nonsyndromic hearing loss 3A Benign:2

Likely benign, criteria provided, single submitter	research	Baylor-Hopkins Center for Mendelian Genomics, Johns Hopkins University School of Medicine	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 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. -

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

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 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 keratitis-ichthyosis-hearing loss syndrome;C0265964:Mutilating keratoderma;C0266004:Knuckle pads, deafness AND leukonychia syndrome;C1835672:Palmoplantar keratoderma-deafness syndrome;C1844678:X-linked mixed hearing loss with perilymphatic gusher;C1865234:Ichthyosis, hystrix-like, with hearing loss;C2673759:Autosomal recessive nonsyndromic hearing loss 1A;C2675750:Autosomal dominant nonsyndromic hearing loss 3A Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 01, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.39
Cadd	Benign	1.5
Dann	Benign	0.69
DEOGEN2	Uncertain	0.47	T;T;T
Eigen	Benign	-1.9
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.10	N
M_CAP	Pathogenic	0.75	D
MetaRNN	Benign	0.014	T;T;T
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Benign	-0.30	N;N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.45	T
PROVEAN	Benign	0.79	N;N;.
REVEL	Benign	0.24
Sift	Benign	0.55	T;T;.
Sift4G	Benign	0.67	T;T;.
Polyphen		0.0	B;B;B
Vest4		0.036
MVP		0.55
MPC		0.042
ClinPred		0.013	T
GERP RS		-9.9
Varity_R		0.024
gMVP		0.70

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: rs111033188; hg19: chr13-20763353;