11-67519840-A-G

Variant names:

• chr11-67519840-A-G
• rs145369252
• NM_016366.3:c.590T>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:3
• Conservation: PhyloP100: 8.73

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 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 rank	MANE	Protein	UniProt
CABP2	NM_016366.3	c.590T>C	p.Ile197Thr	missense_variant	Exon 6 of 7	ENST00000294288.5	NP_057450.2
CABP2	NM_001318496.2	c.608T>C	p.Ile203Thr	missense_variant	Exon 6 of 7		NP_001305425.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CABP2	ENST00000294288.5	c.590T>C	p.Ile197Thr	missense_variant	Exon 6 of 7	1	NM_016366.3	ENSP00000294288.4

Frequencies

GnomAD3 genomes AF: 0.000664 AC: 101 AN: 152114 Hom.: 0 Cov.: 32

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: 79 AN: 251258 Hom.: 0 AF XY: 0.000383 AC XY: 52 AN XY: 135822

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.: 1 Cov.: 32 AF XY: 0.000362 AC XY: 263 AN XY: 727172

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.: 0 Cov.: 32 AF XY: 0.000618 AC XY: 46 AN XY: 74432

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.: 0

Bravo AF: 0.00103

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000329 AC: 40

EpiCase AF: 0.000545

EpiControl AF: 0.000948

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:1

Nov 06, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed in apparent homozygous state in several unrelated patients with hearing loss referred for genetic testing at GeneDx and in published literature; however, also observed in several homozygous clinically unaffected adult relatives of individuals referred for genetic testing at GeneDx (PMID: 38192829); Identified in association with nonsyndromic hearing loss in an additional publication, however, no patient-specific information is available (PMID: 26445815); 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: 38192829, 26445815) -

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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; external communication, internal data). 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. -

Autosomal recessive nonsyndromic hearing loss 93 Pathogenic:1 Uncertain:1

Feb 13, 2020

Institute of Human Genetics, University of Ulm

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Nov 10, 2023

Daryl Scott Lab, Baylor College of Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Uncertain:1

Sep 13, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	T
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	.;T;.
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.73	T;T;T
M_CAP	Benign	0.061	D
MetaRNN	Benign	0.12	T;T;T
MetaSVM	Uncertain	0.098	D
MutationAssessor	Uncertain	2.7	.;M;.
PrimateAI	Uncertain	0.76	T
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	T
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

Other links and lift over

dbSNP: rs145369252; hg19: chr11-67287311;