rs149712664

Positions:

• chr11-67519792-C-A
• chr11-67519792-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

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

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]

ACMG classification

Verdict is Pathogenic. Variant got 16 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 [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	Protein	UniProt
CABP2	NM_016366.3	c.637+1G>T		splice_donor_variant, intron_variant		ENST00000294288.5	NP_057450.2
CABP2	NM_001318496.2	c.655+1G>T		splice_donor_variant, intron_variant			NP_001305425.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CABP2	ENST00000294288.5	c.637+1G>T		splice_donor_variant, intron_variant		1	NM_016366.3	ENSP00000294288.4
CABP2	ENST00000545205.2	n.*422+1G>T		splice_donor_variant, intron_variant		1		ENSP00000446180.1
CABP2	ENST00000636477.1	c.589+1G>T		splice_donor_variant, intron_variant		5		ENSP00000490746.1
CABP2	ENST00000353903.9	c.466+1G>T		splice_donor_variant, intron_variant		5		ENSP00000312037.4

Frequencies

GnomAD3 genomes AF: 0.000782 AC: 119 AN: 152134 Hom.: 0 Cov.: 32

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

GnomAD3 exomes AF: 0.00102 AC: 255 AN: 251044 Hom.: 0 AF XY: 0.00106 AC XY: 144 AN XY: 135696

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 SAS exome AF: 0.00160

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.: 2 Cov.: 32 AF XY: 0.000988 AC XY: 718 AN XY: 726966

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00140

Gnomad4 FIN exome AF: 0.00386

Gnomad4 NFE exome AF: 0.00100

Gnomad4 OTH exome AF: 0.000745

GnomAD4 genome AF: 0.000782 AC: 119 AN: 152134 Hom.: 0 Cov.: 32 AF XY: 0.000807 AC XY: 60 AN XY: 74320

Gnomad4 AFR AF: 0.000362

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00292

Gnomad4 NFE AF: 0.000970

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000777 Hom.: 0

Bravo AF: 0.000480

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.00110 AC: 134

Asia WGS AF: 0.000866 AC: 3 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

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 93 Pathogenic:9

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	Molecular Diagnostics Lab, Aalborg University Hospital	Jun 01, 2020	- -
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	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 26, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center	May 19, 2023	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 -

not provided Pathogenic:8

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) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 14, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	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	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
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	Clinical Genetics Laboratory, Skane University Hospital Lund	May 27, 2022	- -
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	Mayo Clinic Laboratories, Mayo Clinic	Sep 08, 2022	PP1, PM3, PS4_moderate, PVS1_strong -

CABP2-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 17, 2024

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

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.096	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	32
DANN	Uncertain	0.99
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	1.0	D
GERP RS		4.0

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

LitVar

Other links and lift over

dbSNP: rs149712664; hg19: chr11-67287263;