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rs34988750

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM1BP4_ModerateBP6

The NM_004004.6(GJB2):c.478G>A(p.Gly160Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000699 in 1,614,054 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0010 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00067 ( 1 hom. )

Consequence

GJB2
NM_004004.6 missense

Scores

5
8
5

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:11B:11

Conservation

PhyloP100: 6.12
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 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, 8 uncertain in NM_004004.6
BP4
Computational evidence support a benign effect (MetaRNN=0.12778345).
BP6
Variant 13-20189104-C-T is Benign according to our data. Variant chr13-20189104-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 44755.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=11, Benign=3, Likely_benign=8}. Variant chr13-20189104-C-T is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
GJB2NM_004004.6 linkuse as main transcriptc.478G>A p.Gly160Ser missense_variant 2/2 ENST00000382848.5
GJB2XM_011535049.3 linkuse as main transcriptc.478G>A p.Gly160Ser missense_variant 2/2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
GJB2ENST00000382848.5 linkuse as main transcriptc.478G>A p.Gly160Ser missense_variant 2/21 NM_004004.6 P1
GJB2ENST00000382844.2 linkuse as main transcriptc.478G>A p.Gly160Ser missense_variant 1/1 P1

Frequencies

GnomAD3 genomes
AF:
0.00101
AC:
154
AN:
152150
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00217
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000786
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000193
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000705
Gnomad OTH
AF:
0.00143
GnomAD3 exomes
AF:
0.000558
AC:
140
AN:
251098
Hom.:
0
AF XY:
0.000589
AC XY:
80
AN XY:
135738
show subpopulations
Gnomad AFR exome
AF:
0.00228
Gnomad AMR exome
AF:
0.000434
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000218
Gnomad SAS exome
AF:
0.0000653
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000617
Gnomad OTH exome
AF:
0.00196
GnomAD4 exome
AF:
0.000667
AC:
975
AN:
1461786
Hom.:
1
Cov.:
33
AF XY:
0.000635
AC XY:
462
AN XY:
727174
show subpopulations
Gnomad4 AFR exome
AF:
0.00194
Gnomad4 AMR exome
AF:
0.000581
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000227
Gnomad4 SAS exome
AF:
0.0000812
Gnomad4 FIN exome
AF:
0.0000375
Gnomad4 NFE exome
AF:
0.000711
Gnomad4 OTH exome
AF:
0.000977
GnomAD4 genome
AF:
0.00101
AC:
154
AN:
152268
Hom.:
0
Cov.:
33
AF XY:
0.00101
AC XY:
75
AN XY:
74462
show subpopulations
Gnomad4 AFR
AF:
0.00217
Gnomad4 AMR
AF:
0.000785
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000706
Gnomad4 OTH
AF:
0.00142
Alfa
AF:
0.000789
Hom.:
0
Bravo
AF:
0.00120
TwinsUK
AF:
0.000539
AC:
2
ALSPAC
AF:
0.000778
AC:
3
ESP6500AA
AF:
0.00136
AC:
6
ESP6500EA
AF:
0.000465
AC:
4
ExAC
AF:
0.000527
AC:
64
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.000709
EpiControl
AF:
0.00113

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:11Benign:11
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:4Benign:2
Uncertain significance, criteria provided, single submitterclinical testingMayo Clinic Laboratories, Mayo ClinicOct 20, 2022BS1_supporting, PP3 -
Uncertain significance, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesSep 16, 2019The GJB2 c.478G>A; p.Gly160Ser variant (rs34988750) is reported heterozygously in several individuals with hearing loss who also carry one copy of a pathogenic GJB2 variant (Snoeckx 2005), but phase was not reported; however, p.Gly160Ser has also been reported in cis to a pathogenic GJB2 variant in several individuals (Zheng 2015). The p.Gly160Ser variant is found in the African population with an overall allele frequency of 0.22% (55/24922 alleles) in the Genome Aggregation Database and it is reported in ClinVar (Variation ID: 44755). The glycine at codon 160 is highly conserved, and computational analyses (SIFT: tolerated, PolyPhen-2: damaging) predict conflicting effects of this variant on protein structure/function. However, given the lack of clinical and functional data, the significance of the p.Gly160Ser variant is uncertain at this time. References: Snoeckx RL et al. GJB2 mutations and degree of hearing loss: a multicenter study. Am J Hum Genet. 2005 Dec;77(6):945-57. Zheng J et al. GJB2 Mutation Spectrum and Genotype-Phenotype Correlation in 1067 Han Chinese Subjects with Non-Syndromic Hearing Loss. PLoS One. 2015 Jun 4;10(6):e0128691. -
Uncertain significance, criteria provided, single submitterclinical testingAthena DiagnosticsOct 08, 2021- -
Likely benign, criteria provided, single submitterclinical testingInvitaeJan 30, 2024- -
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenJun 01, 2020- -
Uncertain significance, criteria provided, single submitterclinical testingGeneDxMar 22, 2023Observed several times with another pathogenic variant (phase unknown) and once in the homozygous state in patients with hearing loss in published literature (Roux et al., 2004; Snoeckx et al., 2005; Khalifa et al., 2012).; Observed in the heterozygous state with no other pathogenic GJB2 variant in many patients with hearing loss in published literature (Janecke et al., 2002; Gasmelseed et al., 2004; Tang et al., 2006; Batissoco et al., 2009); Variant does not have significant effects on gap junction communication in vitro (Hoang et al., 2009) and has been considered a benign polymorphism (Kenneson et al., 2002; Han et al., 2008); 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: 12172392, 27153395, 16222667, 17660464, 22567861, 17426645, 9600457, 25388846, 25266519, 19043807, 17041943, 12172394, 15365987, 14722929, 19125024, 26043044, 19887791, 24529908, 30245029, 22103400, 16380907, 11313763, 21162657, 33096615, 31992338, 31620696, 31569309, 34338889, 27785406, 12189487, 15070423, 36579563, 19230829) -
Autosomal recessive nonsyndromic hearing loss 1A Uncertain:3Benign:1
Uncertain significance, criteria provided, single submitterclinical testingBaylor GeneticsSep 20, 2019This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
Uncertain significance, criteria provided, single submitterclinical testingCounsylApr 09, 2018- -
Uncertain significance, criteria provided, single submitterclinical testingGenome-Nilou LabJul 14, 2021- -
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017This 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 specified Benign:4
Benign, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Dec 18, 2012- -
Benign, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineDec 17, 2010Gly160Ser in exon 2 of GJB2: This variant has been identified at a frequency of 0.1-0.5% in several studies of individuals with hearing loss (Janecke 2002, Bati ssoco 2008, Gasmelseed 2004, Ross 2007). However, in none of these individuals w as a second GJB2 variant identified. In addition, this variant has been identifi ed in 3/140 (2%) controls (Scott 1998, rs34988750). In summary, the Gly160Ser va riant is not expected to have clinical or pathological significance due to its o ccurrence at a lower frequency in cases compared to controls. -
Likely benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpJan 12, 2024Variant summary: GJB2 c.478G>A (p.Gly160Ser) results in a non-conservative amino acid change located in the 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 allele was found at a frequency of 0.0007 in 1622152 control chromosomes including one homozygote, predominantly at a frequency of 0.0021 within the African or African-American subpopulation in the gnomAD database (v4.0.0). TThis frequency is about 85-fold higher than the estimated maximum for a pathogenic variant in GJB2 causing Autosomal Dominant Non-Syndromic Hearing Loss (NSHL) (0.0022 vs. 2.5E-05), that rules out the dominant inheritance mode for the variant. However, this frequency is not higher than expected for a pathogenic variant in GJB2 causing Autosomal Recessive NSHL (0.0022 vs. 0.025), allowing no conclusion about variant significance for the recessive mode of inheritance. Additional evidence supporting the benign nature of this variant comes from a study which identified the variant in 7/7401 North American hearing loss patients (Putcha 2007). This represents a lower allele frequency (0.00047) in the North American hearing loss population, than either the highest observed allele frequency (0.0022) or the overall frequency for diverse ethnicities (0.0006) of the variant in the control cohort (in gnomAD). The variant, c.478G>A, has been reported in the literature in several individuals affected with Non-Syndromic Hearing Loss, however in most of these cases there was no second allele identified, and in some cases the variant was also mentioned to be present in heterozygosity in unaffected family member (e.g. Wu 2002, Janecke 2002, Gasmelseed 2004, Azaiez 2004, Cheng 2005, Tang 2006, Primignani 2009, Ji 2011, Koohiyan_2019, Ozylmaz_2019, Abtahi_2020); therefore these reports do not indicate a pathogenic role for the variant. Though the variant was reported to be found in homozygosity in one patient from an inbred family, no further information (i.e. co-segregation or co-occurrence data) was provided (Khalifa Alkowari 2012). In a few cases the variant was found in compound heterozygosity with a (potentially) pathogenic allele in patients; however, the phase of the variants was not confirmed by parental testing (Snoeckx 2005, Zhang 2011, Yu_2020). Moreover, the variant was also found in a compound heterozygote (V37I/G160S) with normal hearing (Roux 2004), arguing against its pathogenicity. At least two NSHL patients, homozygous for the common disease variant c.235delC, were reported to also carry the variant of interest, indicating the variant to be in the benign spectrum (Jiang 2014, Zheng 2015). 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: 15070423, 17041943, 15365987, 16380907, 14722929, 17426645, 12172394, 12189487, 22695344, 16222667, 9600457, 19371219, 17666888, 19043807, 22103400, 21162657, 19235794, 21366436, 19125024, 31992338, 15832357, 26043044, 24737404, 30245029, 30466042, 31569309, 31620696). ClinVar contains an entry for this variant (Variation ID: 44755). Based on the evidence outlined above, the variant was classified as likely benign. -
Benign, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoFeb 08, 2013- -
Ichthyosis, hystrix-like, with hearing loss Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitterclinical testingGenome-Nilou LabJul 14, 2021- -
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017This 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 nonsyndromic hearing loss 3A Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitterclinical testingGenome-Nilou LabJul 14, 2021- -
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017This 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. -
Autosomal dominant keratitis-ichthyosis-hearing loss syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGenome-Nilou LabJul 14, 2021- -
Nonsyndromic Deafness Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingMolecular Genetics Laboratory, BC Children's and BC Women's HospitalsMay 19, 2017Reported in gene specific databases (davinci.crg.es/deafness/index.php), ClinVar, and the scientific literature as benign. The evidence for this classification is unclear/not provided, but at least in some cases appears to be due to a reported control population allele frequency of 2% (Scott et al., 1998 PMID: 9600457). This variant is reported in population databases at frequencies of up to 0.22% (gnomAD, ExAC). In silico analyses predict an impact on the protein. -
GJB2-related condition Benign:1
Likely benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesMar 05, 2021This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Nonsyndromic genetic hearing loss Benign:1
Likely benign, criteria provided, single submitterclinical testingINGEBI, INGEBI / CONICETAug 31, 2020Based on ACMG/AMP guidelines and Hearing Loss Expert Panel specific criteria: the filter allele frequency of c.478G>A, p.(Gly160Ser) is 0,17% (55/24922 African alleles with 95% CI) from Genome Aggregation Database (http://gnomad.broadinstitute.org; calculated by using inverse allele frequency at https://www.cardiodb.org/allelefrequencyapp/), which meets the BS1_Supporting criteria. Computational analysis predicted a damage impact of the mutation to the protein (REVELscore:0.767) meeting PP3 rule. The p.(Gly160Ser) change has been identified in heterozygous state in several hearing loss individuals among different ethnic groups (PMID: 24158611, 21162657, 24529908, 19371219, 19125024, 17660464, 16222667, 15070423). This variant has been found in two Austrian familial cases which have been tested only for GJB2 gene: the first case with both parents and child affected in which the proband and her father carried the variant in heterozygous state. The second case is composed of three affected family members: mother and her two daughters. The mother carried p.(Gly160Ser) and her two daughters were not available for the study (PMID: 12189487). Hence, the evidence provided was not enough to apply PP1 rule and was not counted. Besides, this variant has been found in cis with a known pathogenic variant in two unrelated patients (PMID: 22103400) meeting BP2 criteria. Finally, p.(Gly160Ser) change was found with p.Val37Ile and c.35delG in two patients but phase unknown applying to PM3 rule. In summary, this variant meets criteria to be classified as likely benign for autosomal recessive non-syndromic hearing loss (BS1_Supporting, PP3, BP2 and PM3) -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.31
BayesDel_addAF
Benign
-0.080
T
BayesDel_noAF
Uncertain
0.11
Cadd
Uncertain
23
Dann
Uncertain
1.0
DEOGEN2
Pathogenic
0.89
D;D;D
Eigen
Pathogenic
0.71
Eigen_PC
Pathogenic
0.70
FATHMM_MKL
Uncertain
0.95
D
M_CAP
Uncertain
0.18
D
MetaRNN
Benign
0.13
T;T;T
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Uncertain
2.8
M;M;M
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.49
T
PROVEAN
Uncertain
-2.6
D;D;.
REVEL
Pathogenic
0.77
Sift
Benign
0.060
T;T;.
Sift4G
Uncertain
0.053
T;T;.
Polyphen
0.97
D;D;D
Vest4
0.42
MVP
0.98
MPC
0.20
ClinPred
0.042
T
GERP RS
5.5
Varity_R
0.60
gMVP
0.92

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: rs34988750; hg19: chr13-20763243; API