rs111033188

Positions:

chr13-20189214-G-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PM1BP4_StrongBP6_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

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: -2.45

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

PM1

In a chain Gap junction beta-2 protein (size 225) in uniprot entity CXB2_HUMAN there are 70 pathogenic changes around while only 16 benign (81%) 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	Protein	UniProt
GJB2	NM_004004.6 linkuse as main transcript	c.368C>A	p.Thr123Asn	missense_variant	2/2	ENST00000382848.5	NP_003995.2
GJB2	XM_011535049.3 linkuse as main transcript	c.368C>A	p.Thr123Asn	missense_variant	2/2		XP_011533351.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GJB2	ENST00000382848.5 linkuse as main transcript	c.368C>A	p.Thr123Asn	missense_variant	2/2	1	NM_004004.6	ENSP00000372299	P1
GJB2	ENST00000382844.2 linkuse as main transcript	c.368C>A	p.Thr123Asn	missense_variant	1/1			ENSP00000372295	P1

Frequencies

GnomAD3 genomes

AF:

0.000210

AC:

AN:

152212

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.000465

AC XY:

AN XY:

135386

show subpopulations

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.:

Cov.:

AF XY:

0.000193

AC XY:

140

AN XY:

727046

show subpopulations

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:

AN:

152330

Hom.:

Cov.:

AF XY:

0.000242

AC XY:

AN XY:

74494

show subpopulations

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.:

Bravo

AF:

0.000283

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000544

AC:

Asia WGS

AF:

0.00231

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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. -
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. -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 10, 2016	- -

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

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) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

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

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

LIST_S2

Benign

0.14

.;.;T

M_CAP

Pathogenic

0.75

MetaRNN

Benign

0.014

T;T;T

MetaSVM

Uncertain

-0.18

MutationAssessor

Benign

-0.30

N;N;N

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.45

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over