13-20189094-A-G

Position:

• chr13-20189094-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP3

This summary comes from the ClinGen Evidence Repository: The c.488T>C (p.Met163Thr) variant in GJB2 is a missense variant predicted to cause a substitution of methionine by threonine at amino acid 163. The highest population minor allele frequency in gnomAD v4.1.0 is 0.0000934 (7/74950) in the African/African-American population, which is higher than the threshold defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss (<0.007%), and thus does not meet the criterion for PM2. The REVEL computational prediction analysis tool produced a score of 0.981, which is above the threshold necessary to apply PP3. This variant has been detected in individuals diagnosed with hearing loss (PMID:17666888), but not in the homozygous state nor in compound heterozygosity with a known pathogenic/likely pathogenic GJB2 variant. The one likely pathogenic entry in ClinVar for this variant, was reported in an infant with an alternative genetic diagnosis explaining respiratory distress and pulmonary hypertension in whom the GJB2 variant was reported at clinician request due to a half-sibling diagnosed with childhood-onset hearing loss (PMID:30755392, SCV000854502.1). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PP3. (ClinGen Hearing Loss VCEP specifications version 2; 11.20.2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA387461043/MONDO:0019497/005

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: GJB2 NM_004004.6 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:4
• Conservation: PhyloP100: 9.27

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 Uncertain_significance. Variant got 1 ACMG points.

• PP3: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GJB2	NM_004004.6	c.488T>C	p.Met163Thr	missense_variant	2/2	ENST00000382848.5	NP_003995.2
GJB2	XM_011535049.3	c.488T>C	p.Met163Thr	missense_variant	2/2		XP_011533351.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GJB2	ENST00000382848.5	c.488T>C	p.Met163Thr	missense_variant	2/2	1	NM_004004.6	ENSP00000372299.4
GJB2	ENST00000382844.2	c.488T>C	p.Met163Thr	missense_variant	1/1	6		ENSP00000372295.1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152230 Hom.: 0 Cov.: 33

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: 5 AN: 1461760 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727168

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: 4 AN: 152230 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74372

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:1 Uncertain:4

Revision: reviewed by expert panel

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

Nov 20, 2024

The c.488T>C (p.Met163Thr) variant in GJB2 is a missense variant predicted to cause a substitution of methionine by threonine at amino acid 163. The highest population minor allele frequency in gnomAD v4.1.0 is 0.0000934 (7/74950) in the African/African-American population, which is higher than the threshold defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss (<0.007%), and thus does not meet the criterion for PM2. The REVEL computational prediction analysis tool produced a score of 0.981, which is above the threshold necessary to apply PP3. This variant has been detected in individuals diagnosed with hearing loss (PMID: 17666888), but not in the homozygous state nor in compound heterozygosity with a known pathogenic/likely pathogenic GJB2 variant. The one likely pathogenic entry in ClinVar for this variant, was reported in an infant with an alternative genetic diagnosis explaining respiratory distress and pulmonary hypertension in whom the GJB2 variant was reported at clinician request due to a half-sibling diagnosed with childhood-onset hearing loss (PMID: 30755392, SCV000854502.1). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PP3. (ClinGen Hearing Loss VCEP specifications version 2; 11.20.2024). -

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	D
BayesDel_noAF	Pathogenic	0.54
CADD	Uncertain	24
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	D
LIST_S2	Uncertain	0.95	.;.;D
M_CAP	Pathogenic	0.40	D
MetaRNN	Pathogenic	0.94	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.5	M;M;M
PrimateAI	Uncertain	0.69	T
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	D
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

Other links and lift over

dbSNP: rs1273330603; hg19: chr13-20763233;