chr13-20189107-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM1BP4_Moderate

The NM_004004.6(GJB2):​c.475G>A​(p.Asp159Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000477 in 1,614,000 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000047 ( 0 hom. )

Consequence

GJB2
NM_004004.6 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: -0.0480
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 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=0.20563743).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
GJB2NM_004004.6 linkc.475G>A p.Asp159Asn missense_variant 2/2 ENST00000382848.5 NP_003995.2 P29033H9U1J4
GJB2XM_011535049.3 linkc.475G>A p.Asp159Asn missense_variant 2/2 XP_011533351.1 P29033H9U1J4

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
GJB2ENST00000382848.5 linkc.475G>A p.Asp159Asn missense_variant 2/21 NM_004004.6 ENSP00000372299.4 P29033
GJB2ENST00000382844.2 linkc.475G>A p.Asp159Asn missense_variant 1/16 ENSP00000372295.1 P29033

Frequencies

GnomAD3 genomes
AF:
0.0000526
AC:
8
AN:
152204
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
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:
0.0000882
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000836
AC:
21
AN:
251088
Hom.:
0
AF XY:
0.000103
AC XY:
14
AN XY:
135726
show subpopulations
Gnomad AFR exome
AF:
0.0000617
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000176
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000472
AC:
69
AN:
1461796
Hom.:
0
Cov.:
33
AF XY:
0.0000413
AC XY:
30
AN XY:
727184
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:
0.0000375
Gnomad4 NFE exome
AF:
0.0000576
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000526
AC:
8
AN:
152204
Hom.:
0
Cov.:
33
AF XY:
0.0000403
AC XY:
3
AN XY:
74352
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000882
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000818
Hom.:
0
Bravo
AF:
0.0000793
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.000132
AC:
16
EpiCase
AF:
0.00
EpiControl
AF:
0.000119

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 1A Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingGenomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of PhiladelphiaMay 09, 2017- -
Uncertain significance, criteria provided, single submitterclinical testingMyriad Genetics, Inc.Nov 09, 2021NM_004004.5(GJB2):c.475G>A(D159N) is a missense variant classified as a variant of uncertain significance in the context of GJB2-related DFNB1 nonsyndromic hearing loss and deafness. D159N has been observed in cases with relevant disease (PMID: 19366456, 17666888, 14985372). Functional assessments of this variant are available in the literature (PMID: 17077310). D159N has been observed in population frequency databases (gnomAD: NFE 0.02%). In summary, there is insufficient evidence to classify NM_004004.5(GJB2):c.475G>A(D159N) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening. -
not provided Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpMay 02, 2024This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 159 of the GJB2 protein (p.Asp159Asn). This variant is present in population databases (rs373684994, gnomAD 0.02%). This missense change has been observed in individual(s) with deafness (PMID: 16380907, 17666888, 25493717). ClinVar contains an entry for this variant (Variation ID: 438618). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The asparagine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. This variant disrupts the p.Asp159 amino acid residue in GJB2. Other variant(s) that disrupt this residue have been observed in individuals with GJB2-related conditions (Invitae), which suggests that this may be a clinically significant amino acid residue. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitterclinical testingGeneDxNov 19, 2020Observed in patients with hearing loss in published literature; limited information is available for these patients, and the variant was observed with no other GJB2 variant in at least one case (Cryns et al., 2004; Snoeckx et al., 2005; Dai et al., 2009; Qing et al., 2015); In vitro functional studies suggest the variant does not affect voltage-activation of hemichannels; however, data was not available for review (Daniel et al., 2006); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25087612, 19366456, 25493717, 16380907, 14985372, 25388846, 17077310, 17666888, 17041943) -
not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpJul 28, 2022Variant summary: GJB2 c.475G>A (p.Asp159Asn) results in a conservative amino acid change located in the Connexin, N-terminal domain (IPR013092) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8.4e-05 in 251088 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in GJB2 causing Non-Syndromic Hearing Loss (8.4e-05 vs 0.00034), allowing no conclusion about variant significance. c.475G>A has been reported in the literature in cohorts with hearing loss (example, Cryns_2004, Snoeckx_2005, Putcha_2007, Dai_2009, Qing_2015). These report(s) do 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. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.079
BayesDel_addAF
Benign
-0.25
T
BayesDel_noAF
Benign
-0.33
CADD
Benign
15
DANN
Benign
0.81
DEOGEN2
Uncertain
0.62
D;D;D
Eigen
Benign
-0.88
Eigen_PC
Benign
-0.77
FATHMM_MKL
Benign
0.15
N
LIST_S2
Benign
0.70
.;.;T
M_CAP
Benign
0.043
D
MetaRNN
Benign
0.21
T;T;T
MetaSVM
Benign
-0.31
T
MutationAssessor
Benign
0.57
N;N;N
PrimateAI
Benign
0.34
T
PROVEAN
Benign
-1.2
N;N;.
REVEL
Benign
0.25
Sift
Benign
0.74
T;T;.
Sift4G
Benign
0.64
T;T;.
Polyphen
0.0
B;B;B
Vest4
0.061
MVP
0.81
MPC
0.038
ClinPred
0.026
T
GERP RS
3.1
Varity_R
0.063
gMVP
0.74

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.

Other links and lift over

dbSNP: rs373684994; hg19: chr13-20763246; API