rs149712664

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 16P and 1B. PVS1PP5_Very_StrongBS2_Supporting

The NM_016366.3(CABP2):c.637+1G>T variant causes a splice donor, intron 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, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:19

Conservation

PhyloP100: 7.39

Publications

12 publications found

Variant links:

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]

CABP2 Gene-Disease associations (from GenCC):

nonsyndromic genetic hearing loss
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
autosomal recessive nonsyndromic hearing loss 93
Inheritance: AR Classification: STRONG Submitted by: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae)
hearing loss, autosomal recessive
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

CABP2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 15 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.

PP5

Variant 11-67519792-C-A is Pathogenic according to our data. Variant chr11-67519792-C-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 597198.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAdExome4 at 2 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CABP2	NM_016366.3 link	c.637+1G>T		splice_donor_variant, intron_variant	Intron 6 of 6	ENST00000294288.5	NP_057450.2
CABP2	NM_001318496.2 link	c.655+1G>T		splice_donor_variant, intron_variant	Intron 6 of 6		NP_001305425.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
CABP2	ENST00000294288.5 link	c.637+1G>T	splice_donor_variant, intron_variant	Intron 6 of 6	1	NM_016366.3	ENSP00000294288.4
CABP2	ENST00000545205.2 link	n.*422+1G>T	splice_donor_variant, intron_variant	Intron 6 of 6	1		ENSP00000446180.1
CABP2	ENST00000636477.1 link	c.589+1G>T	splice_donor_variant, intron_variant	Intron 5 of 5	5		ENSP00000490746.1
CABP2	ENST00000353903.9 link	c.466+1G>T	splice_donor_variant, intron_variant	Intron 5 of 5	5		ENSP00000312037.4

Frequencies

GnomAD3 genomes

AF:

0.000782

AC:

119

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000362

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00292

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000970

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.00102

AC:

255

AN:

251044

AF XY:

0.00106

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.0000868

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00343

Gnomad NFE exome

AF:

0.00107

Gnomad OTH exome

AF:

0.000654

GnomAD4 exome

AF:

0.00102

AC:

1497

AN:

1461398

Hom.:

Cov.:

AF XY:

0.000988

AC XY:

718

AN XY:

726966

show subpopulations

African (AFR)

AF:

0.000149

AC:

AN:

33470

American (AMR)

AF:

0.000112

AC:

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26114

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00140

AC:

121

AN:

86236

European-Finnish (FIN)

AF:

0.00386

AC:

206

AN:

53354

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.00100

AC:

1114

AN:

1111688

Other (OTH)

AF:

0.000745

AC:

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

160

241

321

401

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

160

200

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000782

AC:

119

AN:

152134

Hom.:

Cov.:

AF XY:

0.000807

AC XY:

AN XY:

74320

show subpopulations

African (AFR)

AF:

0.000362

AC:

AN:

41412

American (AMR)

AF:

0.000131

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.000193

AC:

AN:

5190

South Asian (SAS)

AF:

0.000621

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00292

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000970

AC:

AN:

68028

Other (OTH)

AF:

0.000478

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000763

Hom.:

Bravo

AF:

0.000480

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00105

AC:

ExAC

AF:

0.00110

AC:

134

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.000818

EpiControl

AF:

0.00101

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:19

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 93

Pathogenic:9

Jun 01, 2020

Molecular Diagnostics Lab, Aalborg University Hospital

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Center for Statistical Genetics, Columbia University

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Baylor-Hopkins Center for Mendelian Genomics, Johns Hopkins University School of Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Jan 27, 2020

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 26, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 19, 2023

Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence variant is a single nucleotide substitution (G>T) at the +1 canonical donor splice site of the sixth of seven exons of the CABP2 gene. The disruption of this donor site is expected to lead to the out of frame skipping of exon 6 resulting in the production of a truncated protein that lacks the calcium binding domains critical for calcium sensing by CABP2 (PMID: 22981119). This is a previously reported variant (ClinVar) that has been observed in individuals with hearing loss (PMID: 33666369, 32681043, 30303587). In addition, this variant segregated with hearing loss across multiple individuals in multiple families (PMID: 22981119, 32991204, 35150090, 33269433). This variant is present in 291 of 282,396 alleles (0.1%) in the gnomAD control population dataset. This variant is particularly common in the European Finnish population (0.3%); this relatively high minor allele frequency is attributed to stochastic demographic processes (PMID: 35150090). R, protein, and whole cell alysis confirms that this variant results in the skipping of exon 6, alters calcium affinity of the protein product, and disrupts calcium dependent ictivation of calcium channels (PMID: 22981119). Given this information, we consider this a pathogenic variant. ACMG Criteria: PP1, PS3, PVS1 -

Jul 06, 2019

Laboratory of Prof. Karen Avraham, Tel Aviv University

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

Recessive, compound heterozygous with NM_001318496.1: c.250G>A; congenital, variable SNHL -

Mar 01, 2023

Neuberg Centre For Genomic Medicine, NCGM

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Oct 05, 2012

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

not provided

Pathogenic:8

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Dec 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CABP2: PM3:Strong, PP1:Strong, PVS1:Strong, PM2:Supporting, PS3:Supporting -

May 14, 2018

Eurofins Ntd Llc (ga)

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Sep 08, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PP1, PM3, PS4_moderate, PVS1_strong -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 17, 2022

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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) -

May 27, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

CABP2-related disorder

Pathogenic:1

May 17, 2024

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

University of Washington Center for Mendelian Genomics, University of Washington

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Uncertain

0.096

BayesDel_noAF

Pathogenic

0.34

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Pathogenic

0.99

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Pathogenic

1.0

PhyloP100

7.4

GERP RS

4.0

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.94

SpliceAI score (max)

0.95

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.95

Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over