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rs80338940

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1_StrongPP3_StrongPP5_Very_Strong

The NM_004004.6(GJB2):c.-23+1G>A variant causes a splice donor change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00028 in 153,332 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.00028 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00088 ( 0 hom. )

Consequence

GJB2
NM_004004.6 splice_donor

Scores

2
Splicing: ADA: 1.000
2

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:36

Conservation

PhyloP100: 1.12
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 Pathogenic. Variant got 16 ACMG points.

PVS1
Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.22760646 fraction of the gene.
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
Variant 13-20192782-C-T is Pathogenic according to our data. Variant chr13-20192782-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 17029.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-20192782-C-T is described in Lovd as [Likely_pathogenic]. Variant chr13-20192782-C-T is described in Lovd as [Pathogenic]. Variant chr13-20192782-C-T is described in Lovd as [Pathogenic]. Variant chr13-20192782-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
GJB2NM_004004.6 linkuse as main transcriptc.-23+1G>A splice_donor_variant ENST00000382848.5
GJB2XM_011535049.3 linkuse as main transcriptc.-844G>A 5_prime_UTR_variant 1/2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
GJB2ENST00000382848.5 linkuse as main transcriptc.-23+1G>A splice_donor_variant 1 NM_004004.6 P1

Frequencies

GnomAD3 genomes
AF:
0.000276
AC:
42
AN:
152092
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000387
Gnomad SAS
AF:
0.00228
Gnomad FIN
AF:
0.0000944
Gnomad MID
AF:
0.00321
Gnomad NFE
AF:
0.000324
Gnomad OTH
AF:
0.00143
GnomAD4 exome
AF:
0.000883
AC:
1
AN:
1132
Hom.:
0
Cov.:
0
AF XY:
0.00142
AC XY:
1
AN XY:
702
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00183
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.000276
AC:
42
AN:
152200
Hom.:
0
Cov.:
33
AF XY:
0.000349
AC XY:
26
AN XY:
74418
show subpopulations
Gnomad4 AFR
AF:
0.0000481
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000388
Gnomad4 SAS
AF:
0.00228
Gnomad4 FIN
AF:
0.0000944
Gnomad4 NFE
AF:
0.000324
Gnomad4 OTH
AF:
0.00142
Alfa
AF:
0.000162
Hom.:
0
Bravo
AF:
0.000178
Asia WGS
AF:
0.00262
AC:
9
AN:
3452

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:36
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 1A Pathogenic:14
Pathogenic, criteria provided, single submitterclinical testingMGZ Medical Genetics CenterJul 11, 2022- -
Pathogenic, no assertion criteria providedliterature onlyOMIMSep 01, 2011- -
Pathogenic, no assertion criteria providedliterature onlyGeneReviewsJul 14, 2011- -
Pathogenic, criteria provided, single submitterclinical testingGenomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of PhiladelphiaMay 09, 2017- -
Likely pathogenic, criteria provided, single submitterclinical testingFoundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human GeneticsApr 04, 2023A heterozygous 5’ splice site variant in intron 1 of the GJB2 gene that affects the invariant GT donor splice site downstream of exon 1 (c.-23+1G>A; ENST00000382848.5) was detected. The observed variant has previously been reported (as IVS1+1G>A) in patients affected with hearing loss [PMID: 27843504, ClinVar: VCV000017029.72]. This variant has not been reported in the 1000 genomes and gnomdAD (v2) databases and has a minor allele frequency of 0.03% and 0.02% in the gnomAD (v3.1) and topmed databases, respectively. The in-silico prediction of the variant is damaging by MutationTaster2. The reference base is conserved across mammals. In summary, the variant meets our criteria to be classified as likely pathogenic. -
Likely pathogenic, criteria provided, single submitterclinical testingFoundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human GeneticsApr 28, 2023A heterozygous 5’ splice site variant in intron 1 of the GJB2 gene that affects the invariant GT donor splice site downstream of exon 1 was detected. This variant has not been reported in the 1000 genomes and gnomdAD (v2) databases and has a minor allele frequency of 0.03% and 0.02% in the gnomAD (v3.1) and topmed databases, respectively. The in silico prediction of the variant is damaging by MutationTaster2. The reference base is conserved across mammals. In summary, the variant meets our criteria to be classified as likely pathogenic. -
Pathogenic, no assertion criteria providedcase-controlGenetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery, Institute of Otolaryngology, Chinese PLA General HospitalFeb 26, 2019- -
Pathogenic, no assertion criteria providedclinical testingKnight Diagnostic Laboratories, Oregon Health and Sciences UniversityFeb 11, 2015- -
Pathogenic, no assertion criteria providedclinical testingNatera, Inc.Sep 16, 2020- -
Pathogenic, criteria provided, single submitterresearchKing Laboratory, University of WashingtonAug 01, 2020GJB2 c.-23+1G>A is homozygous in a Palestinian child with severe to profound hearing loss (Abu Rayyan 2020). Based on analysis of RNA from the patient, no transcript from the mutant allele was detectable (PMID: 11935342). The variant is not present in 1300 Palestinian controls and absent from gnomAD v2.1.1. -
Pathogenic, criteria provided, single submitterclinical testingIntegrating Genomics into Medicine, Frazer Institute, University Of QueenslandJun 02, 2023- -
Pathogenic, criteria provided, single submitterclinical testingJohns Hopkins Genomics, Johns Hopkins UniversityApr 28, 2023This GJB2 canonical splice variant has been reported in the homozygous or compound heterozygous state in multiple unrelated individuals with autosomal recessive deafness 1A. This variant (rs80338940) is present in a large population dataset (gnomAD v3.1.2: 42/152092 total alleles; 0.03%; no homozygotes), and has been reported in ClinVar (Variation ID 17029). The variant destroys a canonical splice donor site, is predicted to cause abnormal gene splicing and has supporting functional evidence1. We consider c.-23+1G>A in GJB2 to be pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingMyriad Genetics, Inc.Dec 24, 2019NM_004004.5(GJB2):c.-23+1G>A is classified as pathogenic in the context of GJB2-related DFNB1 nonsyndromic hearing loss and deafness. Sources cited for classification include the following: PMID 21776002. Classification of NM_004004.5(GJB2):c.-23+1G>A is based on the following criteria: The variant is located at a canonical splice site, is expected to disrupt gene function and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening. -
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpOct 24, 2016Variant summary: The GJB2 c.-23+1G>A variant (alternatively also known as IVS1+1G>A, -3170G>A, -3201G>A, -3179G>A, and -3172G>A) involves the alteration of the invariant splice donor site in intron 1. 5/5 splice prediction tools predict that this variant eliminates the 5' splicing donor site. The prediction result was confirmed by a functional study; RNA isolated from lymphocytes from the proband carrying c.-23-1G>A variant and subsequent sequencing of cDNA showed no transcript from this allele (Shahin_2002). This variant was found in 21/4256 control chromosomes at a frequency of 0.0049342, which does not exceed the estimated maximal expected allele frequency of a pathogenic GJB2 variant (0.025). This variant has been reported as one of the common pathogenic variants causing ARNSHL in literature with consistent genotype-phenotype data. The variant has also been postulated to originate from and to have a founder effect in central Asia (Barashkov_2011). Multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as Pathogenic. -
not provided Pathogenic:9
Pathogenic, criteria provided, single submitterclinical testingInstitute of Medical Genetics and Applied Genomics, University Hospital TübingenSep 15, 2021- -
Pathogenic, criteria provided, single submitterclinical testingGeneDxNov 03, 2021Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Published functional studies indicate that this variant disrupts splicing and results in no gene transcription (Shahin et al., 2002); Also known IVS1+1G>A; This variant is associated with the following publications: (PMID: 24840842, 24959830, 25012701, 11935342, 31162818, 16650079, 32708339, 10218527, 24793888, 27843504, 27481527, 31160754, 21776002, 31980526, 32747562, 33096615, 29062245, 30030956, 30487145, 31346875, 31195736, 29907799, 30344259, 31541171, 30275481, 33105617) -
Pathogenic, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenAug 01, 2017- -
Pathogenic, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Pathogenic, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Pathogenic, criteria provided, single submitterclinical testingInvitaeJan 31, 2024This sequence change falls in intron 1 of the GJB2 gene. It does not directly change the encoded amino acid sequence of the GJB2 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs80338940, gnomAD 0.03%). This variant has been observed in individual(s) with deafness (PMID: 10218527, 11935342, 21776002, 24840842, 24959830, 27481527, 27843504). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It is commonly reported in individuals of Yakut ancestry (PMID: 21776002). ClinVar contains an entry for this variant (Variation ID: 17029). Studies have shown that this variant alters GJB2 gene expression (PMID: 11935342). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingAthena Diagnostics IncMar 23, 2022This variant is expected to severely impact normal RNA splicing, and consequently, protein structure and/or function. The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). The variant is a common founder originating from Eastern Siberia (PMID: 21776002). This variant is also referred to as IVS1+1G>A, -3170G>A, -3201G>A, -3179G>A, or -3172G>A in published literature. Assessment of experimental evidence suggests this variant results in abnormal protein function. RNA studies performed on patient lymphocytes yielded no detectable transcript (PMID: 11935342). 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. -
Pathogenic, criteria provided, single submitterclinical testingRevvity Omics, RevvityDec 21, 2023- -
Pathogenic, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesFeb 12, 2021The GJB2 c.-23+1G>A variant (rs80338940), also known as IVS-1+1G>A, has been reported in individuals with autosomal recessive deafness (Barashkov 2011, Denoyelle 1999, Shahin 2002). Functional characterization of the variant indicates an absence of detectable transcript in the patient (Shahin 2002). The variant is listed as pathogenic in ClinVar (Variation ID: 17029), and observed 5 times in the Genome Aggregation Database general population database (5/30850 alleles). The variant is located in the splice consensus site, and computational algorithms (GeneSplicer, Human Splicing Finder, MaxEntScan, MutationTaster, NetGene2, NNSplice, SpliceSiteFinder-like) predict the loss of the canonical splice donor. Based on the above information, the variant is classified as pathogenic. References: Barashkov N et al. Autosomal recessive deafness 1A (DFNB1A) in Yakut population isolate in Eastern Siberia: extensive accumulation of the splice site mutation IVS1+1G>A in GJB2 gene as a result of founder effect. J Hum Genet. 2011; 56(9):631-9. Denoyelle F et al. Clinical features of the prevalent form of childhood deafness, DFNB1, due to a connexin-26 gene defect: implications for genetic counselling. Lancet. 1999; 353(9161):1298-303. Shahin H et al. Genetics of congenital deafness in the Palestinian population: multiple connexin 26 alleles with shared origins in the Middle East. Hum Genet. 2002; 110(3):284-9. -
Autosomal dominant nonsyndromic hearing loss 3A Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsMar 23, 2022- -
Pathogenic, criteria provided, single submitterclinical testingLifecell International Pvt. Ltd-A Heterozygous Splice site donor variant c.-23+1G>A in Exon 1 of the GJB2 gene that results in the amino acid substitution was identified. The observed variant has a maximum allele frequency is novel in gnomAD exomes and 0.00019% in genomes, respectively. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic [Variation ID: 17029]. The literature have been suggesting that, heterozygosity for a GJB2 or GJB6 mutation connotes carrier status for NSHL and rarely can cause autosomal dominant hearing loss by Vassos Neocleous et al., 2014. For these reasons, this variant has been classified as Pathogenic. -
Hearing impairment Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoFeb 08, 2013- -
Pathogenic, criteria provided, single submitterclinical testingDepartment of Otolaryngology – Head & Neck Surgery, Cochlear Implant CenterApr 12, 2021PVS1_Strong, PS1_Strong, PM3_Moderate, BP4_Supporting -
Hearing loss Pathogenic:1
Pathogenic, no assertion criteria providedclinical testingClinical Molecular Genetics Laboratory, Johns Hopkins All Children's HospitalAug 14, 2017- -
GJB2-related condition Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesFeb 14, 2024The GJB2 c.-23+1G>A variant is located in the 5' untranslated region. This variant is also described as c.-3170G>A or IVS1+1G>A. This variant has been reported to be causative for autosomal recessive nonsyndromic hearing loss (Denoyelle et al. 1999. PubMed ID: 10218527; Barashkov et al. 2011. PubMed ID: 21776002; Barashkov et al. 2014. PubMed ID: 24959830). This variant is reported in 0.032% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -
Nonsyndromic genetic hearing loss Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingINGEBI, INGEBI / CONICETAug 21, 2020Based on ACMG/AMP guidelines and Hearing Loss Expert Panel specific criteria: the c.-23+1G>A variant in GJB2 gene is absent from population databases (gnomAD, GO-ESP, 1000 genomes) meeting PM2 criteria. This type of variant is predicted to generate a loss of the donor splicing site in GJB2 gene , which is a known mechanism of disease (PVS1). The c.-23+1G>A variant has been identified in trans with at least 4 pathogenic variants in hearing loss patients applying to PM3_VeryStrong rule (PMID: 10218527, 11313763, 16380907). It was demonstrated that this genetic variant disrupted splicing, yielding no detectable message by sequencing the cDNA from lymphoblastoid cell line of J3 from mutant allele, meeting PS3_Supporting criteria (PMID: 11935342). Therefore, the c.23-23+1G>A variant meets criteria to be classified as pathogenic for autosomal recessive non-syndromic hearing loss (PM2, PVS1, PM3_VerySrong, PS3_Supporting) -
Autosomal recessive nonsyndromic hearing loss 1A;C2675235:Autosomal recessive nonsyndromic hearing loss 1B Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingBaylor Genetics-- -
Autosomal recessive nonsyndromic hearing loss 104 Pathogenic:1
Pathogenic, criteria provided, single submitternot providedInstitute of Human Genetics, University Hospital of Duesseldorf-- -
Hearing loss, autosomal recessive Pathogenic:1
Likely pathogenic, no assertion criteria providedresearchUniversity of Washington Center for Mendelian Genomics, University of Washington-- -
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 submitterclinical testingFulgent Genetics, Fulgent GeneticsJul 06, 2021- -
Ear malformation Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingKariminejad - Najmabadi Pathology & Genetics CenterJul 10, 2021- -
Rare genetic deafness Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineJan 03, 2014The c.-23+1G>A variant in GJB2 has been reported in many probands with hearing l oss (Denoyelle 1999, Shahin 2002, Sirmaci 2006, Yuan 2010, Barashkov 2011). Most of these probands were homozygous or compound heterozygous. In addition, functi onal studies have shown that this variant disrupts splicing, yielding no detecta ble mRNA (Shahin 2002). In summary, this variant meets our criteria to be classi fied as pathogenic. ACMG/AMP Criteria applied: PM3_VeryStrong; PS3 -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.67
Cadd
Uncertain
23
Dann
Benign
0.93

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.84
SpliceAI score (max)
1.0
Details are displayed if max score is > 0.2
DS_DL_spliceai
1.0
Position offset: 1

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: rs80338940; hg19: chr13-20766921; API