rs149712664
Variant summary
Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1PP3_StrongPP5_Very_Strong
The NM_016366.3(CABP2):c.637+1G>T variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.001 in 1,613,532 control chromosomes in the GnomAD database, including 2 homozygotes. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.00078 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0010 ( 2 hom. )
Consequence
CABP2
NM_016366.3 splice_donor
NM_016366.3 splice_donor
Scores
4
2
1
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 7.39
Genes affected
CABP2 (HGNC:1385): (calcium binding protein 2) This gene belongs to a subfamily of calcium binding proteins that share similarity to calmodulin. Like calmodulin, these family members can likely stimulate calmodulin-dependent kinase II and the protein phosphatase calcineurin. Calcium binding proteins are an important component of calcium mediated cellular signal transduction. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2016]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 20 ACMG points.
PVS1
?
Splicing variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
?
Variant 11-67519792-C-A is Pathogenic according to our data. Variant chr11-67519792-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 597198.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-67519792-C-A is described in Lovd as [Pathogenic]. Variant chr11-67519792-C-A is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CABP2 | NM_016366.3 | c.637+1G>T | splice_donor_variant | ENST00000294288.5 | |||
CABP2 | NM_001318496.2 | c.655+1G>T | splice_donor_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CABP2 | ENST00000294288.5 | c.637+1G>T | splice_donor_variant | 1 | NM_016366.3 | ||||
CABP2 | ENST00000545205.2 | c.*422+1G>T | splice_donor_variant, NMD_transcript_variant | 1 | |||||
CABP2 | ENST00000353903.9 | c.466+1G>T | splice_donor_variant | 5 | P1 | ||||
CABP2 | ENST00000636477.1 | c.589+1G>T | splice_donor_variant | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.000782 AC: 119AN: 152134Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00102 AC: 255AN: 251044Hom.: 0 AF XY: 0.00106 AC XY: 144AN XY: 135696
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GnomAD4 exome AF: 0.00102 AC: 1497AN: 1461398Hom.: 2 Cov.: 32 AF XY: 0.000988 AC XY: 718AN XY: 726966
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:17
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Autosomal recessive nonsyndromic hearing loss 93 Pathogenic:8
Pathogenic, no assertion criteria provided | research | Laboratory of Prof. Karen Avraham, Tel Aviv University | Jul 06, 2019 | Recessive, compound heterozygous with NM_001318496.1: c.250G>A; congenital, variable SNHL - |
Pathogenic, criteria provided, single submitter | research | Baylor-Hopkins Center for Mendelian Genomics, Johns Hopkins University School of Medicine | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | Mar 01, 2023 | The invariant splice donor c.637+1G>T variant in CABP2 gene has been observed homozygous / compound heterozygous state in individual(s) with deafness (Schrauwen et. al., 2012). It has also been observed to segregate with disease in related individuals. Studies have shown that disruption of this splice site results in skipping of exon 6 and introduces a new termination codon (Schrauwen et. al., 2012). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (Buratti et. al., 2007). The c.637+1G>T variant is novel (not in any individuals) in 1000 Genomes and has allele frequency of 0.1% in gnomAD exomes database. This variant has been reported to the ClinVar database as Likely Pathogenic / Pathogenic (multiple submitters). For these reasons, this variant has been classified as Pathogenic. In the absence of another reportable variant in CABP2 gene, the molecular diagnosis is not confirmed. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 05, 2012 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Molecular Diagnostics Lab, Aalborg University Hospital | Jun 01, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Center for Statistical Genetics, Columbia University | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jan 27, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Mar 26, 2024 | - - |
not provided Pathogenic:7
Likely pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | May 14, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 17, 2022 | Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 30096381, 22981119, 31053783, 30303587, 31661684, 33269433, 32991204, 32681043, 32860223, 33666369) - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Feb 01, 2024 | CABP2: PM3:Strong, PP1:Strong, PVS1:Strong, PS3:Moderate, PM2:Supporting - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | This sequence change affects a donor splice site in intron 6 of the CABP2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely disrupts the C-terminus of the protein. This variant is present in population databases (rs149712664, gnomAD 0.4%), and has an allele count higher than expected for a pathogenic variant. Disruption of this splice site has been observed in individual(s) with deafness (PMID: 22981119). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 597198). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that disruption of this splice site results in skipping of exon 6 and introduces a new termination codon (PMID: 22981119). However the mRNA is not expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
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 | Mayo Clinic Laboratories, Mayo Clinic | Sep 08, 2022 | PP1, PM3, PS4_moderate, PVS1_strong - |
CABP2-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Dec 18, 2023 | The CABP2 c.637+1G>T variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant segregated with autosomal recessive hearing loss in seven families with 15 affected and 11 unaffected individuals (Schrauwen. 2012. PubMed ID: 22981119; Ramzan. 2020. PubMed ID: 32681043; Sheyanth. 2021. PubMed ID: 33666369; Bharadwaj. 2022. PubMed ID: 35150090). This variant is reported in 0.33% of alleles in individuals of European (Finnish) descent in gnomAD. This variant is interpreted as pathogenic. - |
Hearing loss, autosomal recessive Pathogenic:1
Likely pathogenic, no assertion criteria provided | research | University of Washington Center for Mendelian Genomics, University of Washington | - | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
D;D
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: 1
Find out detailed SpliceAI scores and Pangolin per-transcript scores at