11-67519840-A-G

Position:

chr11-67519840-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_016366.3(CABP2):c.590T>C(p.Ile197Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000377 in 1,613,984 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00035 ( 1 hom. )

Consequence

CABP2
NM_016366.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:3

Conservation

PhyloP100: 8.73

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.12365916).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CABP2	NM_016366.3 linkuse as main transcript	c.590T>C	p.Ile197Thr	missense_variant	6/7	ENST00000294288.5
CABP2	NM_001318496.2 linkuse as main transcript	c.608T>C	p.Ile203Thr	missense_variant	6/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CABP2	ENST00000294288.5 linkuse as main transcript	c.590T>C	p.Ile197Thr	missense_variant	6/7	1	NM_016366.3		Q9NPB3-1
CABP2	ENST00000545205.2 linkuse as main transcript	c.*375T>C		3_prime_UTR_variant, NMD_transcript_variant	6/7	1
CABP2	ENST00000636477.1 linkuse as main transcript	c.542T>C	p.Ile181Thr	missense_variant	5/6	5
CABP2	ENST00000353903.9 linkuse as main transcript	c.419T>C	p.Ile140Thr	missense_variant	5/6	5		P1	Q9NPB3-2

Frequencies

GnomAD3 genomes

AF:

0.000664

AC:

101

AN:

152114

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00412

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000441

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.000314

AC:

AN:

251258

Hom.:

AF XY:

0.000383

AC XY:

AN XY:

135822

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000376

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000464

Gnomad NFE exome

AF:

0.000537

Gnomad OTH exome

AF:

0.000652

GnomAD4 exome

AF:

0.000348

AC:

508

AN:

1461752

Hom.:

Cov.:

AF XY:

0.000362

AC XY:

263

AN XY:

727172

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.000805

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.0000562

Gnomad4 NFE exome

AF:

0.000375

Gnomad4 OTH exome

AF:

0.000464

GnomAD4 genome

AF:

0.000663

AC:

101

AN:

152232

Hom.:

Cov.:

AF XY:

0.000618

AC XY:

AN XY:

74432

show subpopulations

Gnomad4 AFR

AF:

0.0000963

Gnomad4 AMR

AF:

0.00412

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000441

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.000283

Hom.:

Bravo

AF:

0.00103

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000329

AC:

EpiCase

AF:

0.000545

EpiControl

AF:

0.000948

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 30, 2023	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 197 of the CABP2 protein (p.Ile197Thr). This variant is present in population databases (rs145369252, gnomAD 0.05%). This missense change has been observed in individual(s) with nonsyndromic deafness (PMID: 26445815; Invitae; external communication). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 667198). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. For these reasons, this variant has been classified as Pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 12, 2024	Identified in association with nonsyndromic hearing loss in published literature, however, no patient-specific information is available (PMID: 26445815); Observed in apparent homozygous state in several unrelated patients with hearing loss referred for genetic testing at GeneDx; however, also observed in at least one homozygous clinically unaffected adult relative of an individual referred for genetic testing at GeneDx; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26445815, 38192829) -

Autosomal recessive nonsyndromic hearing loss 93

Pathogenic:1Uncertain:1

Likely pathogenic, no assertion criteria provided	research	Institute of Human Genetics, University of Ulm	Feb 13, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Daryl Scott Lab, Baylor College of Medicine	Nov 10, 2023	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 13, 2018

The p.Ile197Thr variant in CABP2 has been reported in the homozygous state in 1 individual with hearing loss (Sloan-Heggen 2015). It has also been identified in 0.05% (66/126628) of European chromosomes by the Genome Aggregation Database (g nomAD, http://gnomad.broadinstitute.org/). Computational prediction tools and co nservation analysis do not provide strong support for or against an impact to th e protein. In summary, the clinical significance of the p.Ile197Thr variant is u ncertain. ACMG/AMP Criteria applied: PM3_Supporting, PM2_Supporting. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.94

BayesDel_addAF

Benign

-0.039

BayesDel_noAF

Uncertain

0.060

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.29

.;T;.

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Benign

0.73

T;T;T

M_CAP

Benign

0.061

MetaRNN

Benign

0.12

T;T;T

MetaSVM

Uncertain

0.098

MutationAssessor

Uncertain

2.7

.;M;.

MutationTaster

Benign

0.99

D;D

PrimateAI

Uncertain

0.76

PROVEAN

Uncertain

-3.4

D;D;.

REVEL

Pathogenic

0.68

Sift

Uncertain

0.0010

D;D;.

Sift4G

Uncertain

0.0030

D;D;.

Polyphen

0.96

D;P;.

Vest4

0.86

MVP

0.88

MPC

1.0

ClinPred

0.23

GERP RS

4.2

Varity_R

0.52

gMVP

0.88

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over