13-20189166-C-T
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Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PP5_Very_Strong
The NM_004004.6(GJB2):โc.416G>Aโ(p.Ser139Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000631 in 1,614,082 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (โ โ ).
Frequency
Genomes: ๐ 0.00046 ( 0 hom., cov: 33)
Exomes ๐: 0.00065 ( 0 hom. )
Consequence
GJB2
NM_004004.6 missense
NM_004004.6 missense
Scores
4
11
4
Clinical Significance
Conservation
PhyloP100: 7.86
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 Pathogenic. 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
PP5
Variant 13-20189166-C-T is Pathogenic according to our data. Variant chr13-20189166-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 44749.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-20189166-C-T is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| GJB2 | NM_004004.6 | c.416G>A | p.Ser139Asn | missense_variant | 2/2 | ENST00000382848.5 | NP_003995.2 | |
| GJB2 | XM_011535049.3 | c.416G>A | p.Ser139Asn | missense_variant | 2/2 | XP_011533351.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| GJB2 | ENST00000382848.5 | c.416G>A | p.Ser139Asn | missense_variant | 2/2 | 1 | NM_004004.6 | ENSP00000372299 | P1 | |
| GJB2 | ENST00000382844.2 | c.416G>A | p.Ser139Asn | missense_variant | 1/1 | ENSP00000372295 | P1 |
Frequencies
GnomAD3 genomes 0.000460 AC: 70AN: 152202Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000295 AC: 74AN: 250946Hom.: 0 AF XY: 0.000287 AC XY: 39AN XY: 135726
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GnomAD4 exome AF: 0.000649 AC: 949AN: 1461762Hom.: 0 Cov.: 33 AF XY: 0.000605 AC XY: 440AN XY: 727180
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GnomAD4 genome 0.000460 AC: 70AN: 152320Hom.: 0 Cov.: 33 AF XY: 0.000497 AC XY: 37AN XY: 74476
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:24
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:10
| Likely pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Apr 01, 2019 | - - |
| Likely pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Feb 10, 2021 | The GJB2 c.416G>A; p.Ser139Asn variant (rs76434661) is reported in the literature in multiple unrelated individuals affected with sensorineural hearing loss, and in many individuals a second pathogenic variant was also identified (Dodson 2011, Gao 2016, Li 2014, Marlin 2001, Plevova 2018, Santos 2005, Snoeckx 2005, Tang 2006, Xing 2016). Additionally, the p.Ser139Asn variant is reported to co-segregate with disease in a proband and an affected sibling (Santos 2005), and functional analysis shows the variant protein fails to correctly localize to plasma membrane junctions (Fleishman 2006). This variant is classified as likely pathogenic or pathogenic by multiple laboratories in ClinVar (Variation ID: 44749). It is found in the general population with an overall allele frequency of 0.03% (89/282358 alleles) in the Genome Aggregation Database. The serine at codon 139 is highly conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.633). Based on available information, including its occurrence in multiple affected individuals, this variant is considered to be pathogenic. References: Dodson KM et al. Vestibular dysfunction in DFNB1 deafness. Am J Med Genet A. 2011 May;155A(5):993-1000. Fleishman SJ et al. The structural context of disease-causing mutations in gap junctions. J Biol Chem. 2006 Sep 29;281(39):28958-63. Gao Z et al. Application of SNPscan in Genetic Screening for Common Hearing Loss Genes. PLoS One. 2016 Oct 28;11(10):e0165650. Li Q et al. Comparative study of mutation spectrums of MT-RNR1 m.1555A>G, GJB2, and SLC26A4 between familial and sporadic patients with nonsyndromic sensorineural hearing loss in Chinese Han. Chin Med J (Engl). 2014;127(18):3233-7. Marlin S et al. Connexin 26 gene mutations in congenitally deaf children: pitfalls for genetic counseling. Arch Otolaryngol Head Neck Surg. 2001 Aug;127(8):927-33. Plevova P et al. Genetic Aetiology of Nonsyndromic Hearing Loss in Moravia-Silesia. Medicina (Kaunas). 2018 May 4;54(2):28. Santos RL et al. Hearing impairment in Dutch patients with connexin 26 (GJB2) and connexin 30 (GJB6) mutations. Int J Pediatr Otorhinolaryngol. 2005 Feb;69(2):165-74. Snoeckx RL et al. GJB2 mutations and degree of hearing loss: a multicenter study. Am J Hum Genet. 2005 Dec;77(6):945-57. Tang HY et al. DNA sequence analysis of GJB2, encoding connexin 26: observations from a population of hearing impaired cases and variable carrier rates, complex genotypes, and ethnic stratification of alleles among controls. Am J Med Genet A. 2006 Nov 15;140(22):2401-15. Xing J et al. Genetic and clinical analysis of nonsyndromic hearing impairment in pediatric and adult cases. Balkan J Med Genet. 2016 Aug 2;19(1):35-42. - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 21, 2021 | Also identified in individuals with nonsyndromic hearing loss in whom no second pathogenic variant was identified (Wu et al., 2003; Azaiez et al., 2004; Bonyadi et al., 2014); Published functional studies suggest that the S139N variant is associated with abnormal localization of the protein (Fleishman et al., 2006); 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: 19235794, 20668687, 20083784, 26284228, 12172394, 17666888, 19173109, 20981092, 21162657, 27785406, 27535533, 30275481, 31160754, 16864573, 32003480, 32596493, 20234132, 28483220, 30344259, 26778469, 15365987, 15656949, 16380907, 19366456, 17041943, 26444186, 25266519, 12925341, 16950989, 21465647, 22695344, 24529908, 28576516, 27018795, 29754767, 23891399, 25388846, 27153395, 27792752, 11493200, 22995991, 25087612, 12910486, 24033266) - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Oct 12, 2015 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Aug 19, 2022 | - - |
| Likely pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 31, 2024 | This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 139 of the GJB2 protein (p.Ser139Asn). This variant is present in population databases (rs76434661, gnomAD 0.06%). This missense change has been observed in individuals with hearing loss (PMID: 11493200, 12172394, 16380907, 17041943, 21465647, 27785406). ClinVar contains an entry for this variant (Variation ID: 44749). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GJB2 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects GJB2 function (PMID: 16864573). For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Jul 13, 2021 | The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features associated with this gene. Assessment of experimental evidence suggests this variant results in abnormal protein function. Studies in HeLa cells showed defective localization and coupling (PMID: 16864573). In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. - |
Autosomal recessive nonsyndromic hearing loss 1A Pathogenic:8
| Likely pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Dec 17, 2019 | NM_004004.5(GJB2):c.416G>A(S139N) is classified as likely pathogenic in the context of GJB2-related DFNB1 nonsyndromic hearing loss and deafness. Sources cited for classification include the following: PMID 11493200, 21465647, 25266519, 16950989, 22695344, 20234132, 17041943, 24529908, 12910486 and 12925341. Classification of NM_004004.5(GJB2):c.416G>A(S139N) is based on the following criteria: This variant has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 18, 2022 | Variant summary: GJB2 c.416G>A (p.Ser139Asn) results in a conservative amino acid change located in the Connexin, N-terminal domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00029 in 251378 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in GJB2 causing Autosomal Recessive Non-Syndromic Hearing Loss (0.00029 vs 0.025), allowing no conclusion about variant significance. The variant, c.416G>A, has been reported in the literature in multiple individuals affected with Autosomal Recessive Non-Syndromic Hearing Loss in compound heterozygous state with other pathogenic or potentially pathogenic variants (Marlin_2001, Santos_2005, Snoeckx_2005, Dodson_2011, Burke_2016, Plevova_2018). Additionally, it was found to segregate with disease in two affected siblings in a family (Santos_2005). This variant has also been found in hearing loss patients whose second mutation was not identified (Wu_2002, Azaiez_2004, Dai_2009, Bazazzadegan_2012, Bonyadi_2014). These data indicate that the variant is very likely to be associated with disease. Functional studies in HeLa cells showed defective localization and coupling (Fleishman_2006). 14 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, thirteen have classified as likely pathogenic/pathogenic while one has classified as benign. Based on the evidence outlined above, the variant was classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia | May 09, 2017 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Oct 22, 2018 | Across a selection of the available literature, the c.416G>A (p.Ser139Asn) missense variant has been identified in 13 individuals affected with hearing loss including eight compound heterozygotes (including two siblings), at least five of whom carried another known pathogenic variant in trans and at least six heterozygotes (Marlin et al. 2001; Azaiez et al. 2004; Santos et al. 2005; Snoeckx et al. 2005; Tang et al. 2006; Dai et al. 2009; Dodson et al. 2011; Bonyadi et al. 2014). The p.Ser139Asn variant was absent from 761 controls and is reported at a frequency of 0.00081 in the European American population of the Exome Sequencing Project. Functional studies in HeLa cells transfected with the variant protein showed the p.Ser139Asn variant leads to mislocalization of the protein compared to wild type (Fleishman et al. 2006). Based on the collective evidence, the p.Ser139Asn variant is classified as pathogenic for autosomal recessive non-syndromic hearing loss. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 07, 2021 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Feb 12, 2020 | - - |
| Likely pathogenic, no assertion criteria provided | clinical testing | Center for Molecular Medicine, Childrenโs Hospital of Fudan University | Feb 08, 2022 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Knight Diagnostic Laboratories, Oregon Health and Sciences University | Jan 27, 2016 | The c.416G>A (p.Ser139Asn) missense variant in the GJB2 gene has been previously reported in at least nine individuals with autosomal recessive Nonsyndromic hearing loss and deafness. This c.416G>A variant has been observed in trans with the well-known 35delG variant in an affected individual (Marlin et al., 2001). An in vitro functional study showed this variant affects localization of the protein (Fleishman et al., 2006). The c.229C>T variant has been reported at low frequency in the c population databases (Exome Sequencing Project [ESP] = 0.0.081%, 1000 Genomes = 0.2%, and ExAC = 0.051%). Multiple in silico algorithms predict this variant to have a deleterious effect (GERP = 5.47; CADD = 24.9; PROVEAN = -2.62), and multiple reputable diagnostic laboratories report this variant as pathogenic. Therefore, this collective evidence supports the classification of the c.416G>A (p.Ser139Asn) as a recessive Likely Pathogenic variant for Nonsyndromic hearing loss and deafness. - |
Hearing loss Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital | Jul 31, 2009 | - - |
Hearing impairment Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Feb 08, 2013 | - - |
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 Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 18, 2017 | - - |
Autosomal dominant nonsyndromic hearing loss 3A Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Jun 23, 2016 | - - |
Rare genetic deafness Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jan 31, 2019 | The p.Ser139Asn variant in GJB2 has been reported in at least 10 individuals with hearing loss, at least 7 of whom were homozygous or compound heterozygous (Marlin 2001, Azaiez 2004, Santos 2005, Rikkert 2005, Tang 2006, Dai 2009, Dodson 2011, Li 2014, Bonyadi 2014, Xing 2016, Plevova 2018). Additionally, this variant segregated with disease in one affected relative from one family (Santos 2005). In vitro functional studies support that the p.Ser139Asn variant impacts protein function (Fleishman 2006). Although this variant has been identified in 0.058% (75/128800) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org), its frequency is low enough to be consistent with a recessive carrier frequency. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive hearing loss. ACMG/AMP criteria applied: PM3_VeryStrong, PP1, PP3, PM2_Supporting, PS3_Supporting. - |
Autosomal recessive nonsyndromic hearing loss 1A;C2675235:Autosomal recessive nonsyndromic hearing loss 1B Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | - | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Pathogenic
D;D;D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
.;.;D
M_CAP
Pathogenic
D
MetaRNN
Uncertain
D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
M;M;M
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;.
REVEL
Uncertain
Sift
Benign
T;T;.
Sift4G
Benign
T;T;.
Polyphen
P;P;P
Vest4
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at