rs80338940
Variant names:
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_StrongPP5_Very_Strong
The NM_004004.6(GJB2):c.-23+1G>A variant causes a splice donor, intron 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. 3/3 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, intron
NM_004004.6 splice_donor, intron
Scores
2
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 1.12
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 12 ACMG points.
PVS1
Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.2290749 fraction of the gene.
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 rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| GJB2 | NM_004004.6 | c.-23+1G>A | splice_donor_variant, intron_variant | Intron 1 of 1 | ENST00000382848.5 | NP_003995.2 | ||
| GJB2 | XM_011535049.3 | c.-844G>A | 5_prime_UTR_premature_start_codon_gain_variant | Exon 1 of 2 | XP_011533351.1 | |||
| GJB2 | XM_011535049.3 | c.-844G>A | 5_prime_UTR_variant | Exon 1 of 2 | XP_011533351.1 |
Ensembl
Frequencies
GnomAD3 genomes 0.000276 AC: 42AN: 152092Hom.: 0 Cov.: 33
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:40
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Autosomal recessive nonsyndromic hearing loss 1A Pathogenic:16
| Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 01, 2011 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Jul 11, 2022 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Knight Diagnostic Laboratories, Oregon Health and Sciences University | Feb 11, 2015 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Dec 24, 2019 | NM_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 submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 24, 2016 | Variant 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. - |
| Pathogenic, criteria provided, single submitter | research | King Laboratory, University of Washington | Aug 01, 2020 | GJB2 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 submitter | clinical testing | Johns Hopkins Genomics, Johns Hopkins University | Apr 28, 2023 | This 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 submitter | clinical testing | Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia | May 09, 2017 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
| Pathogenic, no assertion criteria provided | literature only | GeneReviews | Jul 14, 2011 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Integrating Genomics into Medicine, Frazer Institute, University Of Queensland | Jun 02, 2023 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics | Apr 04, 2023 | A 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Oct 10, 2024 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with both deafness and skin conditions (OMIM). Dominant negative is also a suggested mechanism (PMID: 28428247). (I) 0108 - This gene is associated with both recessive and dominant disease. The autosomal dominant diseases are commonly associated with pathogenic missense variants. The autosomal recessive disease is associated with biallelic loss of function variants and includes missense and protein truncating variants (NIH Genetics Home Reference, PMID: 12792423). (I) 0112 - The condition associated with this gene has incomplete penetrance (PMID: 31160754). (I) 0115 - Variants in this gene are known to have variable expressivity. Severity can range from mild to profound with intrafamilial variability also commonly seen. Commonly, truncating variants are associated to a more severe hearing loss (PMID: 20301449). (I) 0211 - Canonical splice site variant without proven consequence on splicing. RNA RT-PCR performed on an affected individual’s lymphocytes who is compound heterozygous for this variant and c.35delG showed the deletion variant was present, however, the splicing effect of c.-23+1G>A was deemed to be inconclusive (PMID: 11935342). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v3) <0.01 for a recessive condition (34 heterozygotes, 0 homozygotes). (SP) 0311 - An alternative nucleotide change at the same canonical splice site is present in gnomAD (v3) at a frequency of 0.000006 (1 heterozygote, 0 homozygote). (I) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. This variant is a well-reported pathogenic variant and has been postulated to have a founder effect in deaf individuals from South Siberian populations (ClinVar, Deafness Variation database, PMID: 37239361, PMID: 32708339). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre | Mar 26, 2024 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics | Apr 28, 2023 | A 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 provided | case-control | Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery, Institute of Otolaryngology, Chinese PLA General Hospital | Feb 26, 2019 | - - |
not provided Pathogenic:10
| 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 | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Sep 15, 2021 | - - |
| 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 | Revvity Omics, Revvity | Dec 21, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Mar 23, 2022 | This 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 submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 07, 2025 | This 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 submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Dec 01, 2024 | GJB2: PM3:Very Strong, PVS1:Strong, PM2, PS3:Supporting - |
| Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Mar 04, 2025 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 03, 2021 | Canonical 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 submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Aug 26, 2024 | The GJB2 c.-23+1G>A variant (rs80338940), also published as IVS1+1G>A and -3170G>A, is reported in the literature in the homozygous and compound heterozygous state in numerous individuals with hearing loss and is described as a founder variant in populations of the Caucasus and northern Asia (Barashkov 2011, Denoyelle 1999, Posukh 2019, Shahin 2002, Solovyev 2022). This variant is found in the general population with an overall allele frequency of 0.02% (6/31,290 alleles) in the Genome Aggregation Database (v2.1.1). This variant disrupts the canonical splice donor site of intron 1, which is likely to negatively impact gene function. Functional characterization in patient lymphocytes indicates an absence of detectable transcript carrying the c.-23+1G>A variant, suggesting the transcript is unstable (Shahin 2002). Based on available information, this variant is considered to be pathogenic. References: Barashkov NA 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 Sep;56(9):631-9. PMID: 21776002. 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 Apr 17;353(9161):1298-303. PMID: 10218527. Posukh OL et al. Unique Mutational Spectrum of the GJB2 Gene and its Pathogenic Contribution to Deafness in Tuvinians (Southern Siberia, Russia): A High Prevalence of Rare Variant c.516G>C (p.Trp172Cys). Genes (Basel). 2019 Jun 5;10(6):429. PMID: 31195736. 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 Mar;110(3):284-9. PMID: 11935342. Solovyev AV et al. A common founder effect of the splice site variant c.-23?+?1G?>?A in GJB2 gene causing autosomal recessive deafness 1A (DFNB1A) in Eurasia. Hum Genet. 2022 Apr;141(3-4):697-707. PMID: 34839402. - |
Autosomal dominant nonsyndromic hearing loss 3A Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Lifecell 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 23, 2022 | - - |
Hearing impairment Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center | Apr 12, 2021 | PVS1_Strong, PS1_Strong, PM3_Moderate, BP4_Supporting - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Feb 08, 2013 | - - |
Hearing loss Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital | Aug 14, 2017 | - - |
Autosomal dominant keratitis-ichthyosis-hearing loss syndrome;C0265964:Mutilating keratoderma;C0266004:Knuckle pads, deafness AND leukonychia syndrome;C1835672:Palmoplantar keratoderma-deafness syndrome;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 | Jun 06, 2024 | - - |
Nonsyndromic genetic hearing loss Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | INGEBI, INGEBI / CONICET | Aug 21, 2020 | Based 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 submitter | clinical testing | Baylor Genetics | - | - - |
GJB2-related disorder Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | May 01, 2024 | The 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 and 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 and is listed as pathogenic in ClinVar by multiple laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/17029/). This variant is interpreted as pathogenic. - |
Autosomal recessive nonsyndromic hearing loss 104 Pathogenic:1
| Pathogenic, criteria provided, single submitter | not provided | Institute of Human Genetics, University Hospital of Duesseldorf | - | - - |
Hearing loss, autosomal recessive Pathogenic:1
| Likely pathogenic, no assertion criteria provided | research | University of Washington Center for Mendelian Genomics, University of Washington | - | - - |
Ear malformation Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Kariminejad - Najmabadi Pathology & Genetics Center | Jul 10, 2021 | - - |
Rare genetic deafness Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 30, 2022 | The c.-23+1G>A variant in GJB2 has been reported in many probands with hearing loss (Denoyelle 1999 PMID: 10218527, Shahin 2002 PMID: 11935342, Sirmaci 2006 PMID: 17406097, Yuan 2010 PMID: 21122151, Barashkov 2011 PMID: 21776002). Most of these probands were homozygous or compound heterozygous. In addition, functional studies have shown that this variant disrupts splicing, yielding no detectable mRNA (Shahin 2002 PMID: 11935342). In summary, this variant meets our criteria to be classified as pathogenic. ACMG/AMP Criteria applied: PM3_VeryStrong; PS3. - |
Hereditary palmoplantar keratoderma Pathogenic:1
| Pathogenic, criteria provided, single submitter | research | Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital | Oct 04, 2024 | PVS1,PS3,PM3(strong),PM2 - |
Computational scores
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Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
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