13-20189094-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM5PP3_Moderate

The NM_004004.6(GJB2):c.488T>C(p.Met163Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,613,990 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M163R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

GJB2
NM_004004.6 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel P:1U:4

Conservation

PhyloP100: 9.27

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 Likely_pathogenic. Variant got 6 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 7 uncertain in NM_004004.6

PM5

Other missense variant is known to change same aminoacid residue: Variant chr13-20189095-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 21388.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=9, Likely_pathogenic=2, not_provided=1}.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.938

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GJB2	NM_004004.6 linkuse as main transcript	c.488T>C	p.Met163Thr	missense_variant	2/2	ENST00000382848.5
GJB2	XM_011535049.3 linkuse as main transcript	c.488T>C	p.Met163Thr	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GJB2	ENST00000382848.5 linkuse as main transcript	c.488T>C	p.Met163Thr	missense_variant	2/2	1	NM_004004.6	P1
GJB2	ENST00000382844.2 linkuse as main transcript	c.488T>C	p.Met163Thr	missense_variant	1/1			P1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152230

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461760

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727168

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152230

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74372

show subpopulations

Gnomad4 AFR

AF:

0.0000965

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:4

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Respiratory distress;C2973725:Pulmonary arterial hypertension;C4281993:Neonatal respiratory distress

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Center for Personalized Medicine, Children's Hospital Los Angeles

- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jul 07, 2023

Variant summary: GJB2 c.488T>C (p.Met163Thr) results in a non-conservative amino acid change located in the gap junction protein, cysteine-rich domain (IPR019570) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251140 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.488T>C has been reported in the literature as an uninformative genotype (i.e. zygosity not specified) in two alleles from a cohort of individuals undergoing genetic testing for autosomal recessive Non-Syndromic Hearing Loss (Putcha_2007). This report does not provide unequivocal conclusions about association of the variant with Non-Syndromic Hearing Loss. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 30755392, 17666888). Three submitters, including the ClinGen Hearing Loss Variant Curation Expert Panel, have cited clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Autosomal recessive nonsyndromic hearing loss 1A

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Feb 12, 2021

- -

Nonsyndromic genetic hearing loss

Uncertain:1

Uncertain significance, reviewed by expert panel

curation

ClinGen Hearing Loss Variant Curation Expert Panel

Apr 29, 2020

The c.488T>C (p.Met163Thr) variant in GJB2 is present in 0.0115% (1/8710) of African chromosomes in gnomAD 2.1.1, which is a low enough frequency to award PM2 based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss (PM2). The REVEL computational prediction analysis tool produced a score of 0.981, which is above the threshold necessary to apply PP3. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PM2, PP3. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Dec 28, 2020

Identified in two individuals from a large cohort of patients with hearing loss in published literature (Putcha et al., 2007); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 17666888, 25388846, 19081147, 30755392) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.92

BayesDel_addAF

Pathogenic

0.54

BayesDel_noAF

Pathogenic

0.54

Cadd

Uncertain

Dann

Uncertain

0.99

DEOGEN2

Pathogenic

0.91

D;D;D

Eigen

Pathogenic

0.94

Eigen_PC

Pathogenic

0.88

FATHMM_MKL

Pathogenic

0.98

M_CAP

Pathogenic

0.40

MetaRNN

Pathogenic

0.94

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.5

M;M;M

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.69

PROVEAN

Uncertain

-4.3

D;D;.

REVEL

Pathogenic

0.98

Sift

Uncertain

0.0010

D;D;.

Sift4G

Pathogenic

0.0010

D;D;.

Polyphen

0.99

D;D;D

Vest4

0.96

MutPred

0.71

Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);

MVP

0.95

MPC

0.25

ClinPred

1.0

GERP RS

5.5

Varity_R

0.93

gMVP

0.94

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