11-67519840-A-G

Variant summary

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

The NM_016366.3(CABP2):ā€‹c.590T>Cā€‹(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: š‘“ 0.00066 ( 0 hom., cov: 32)
Exomes š‘“: 0.00035 ( 1 hom. )

Consequence

CABP2
NM_016366.3 missense

Scores

3
10
6

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]

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 rank MANE Protein UniProt
CABP2NM_016366.3 linkc.590T>C p.Ile197Thr missense_variant Exon 6 of 7 ENST00000294288.5 NP_057450.2 Q9NPB3-1
CABP2NM_001318496.2 linkc.608T>C p.Ile203Thr missense_variant Exon 6 of 7 NP_001305425.1 Q9NPB3F1T0K2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CABP2ENST00000294288.5 linkc.590T>C p.Ile197Thr missense_variant Exon 6 of 7 1 NM_016366.3 ENSP00000294288.4 Q9NPB3-1

Frequencies

GnomAD3 genomes
AF:
0.000664
AC:
101
AN:
152114
Hom.:
0
Cov.:
32
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:
79
AN:
251258
Hom.:
0
AF XY:
0.000383
AC XY:
52
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.:
1
Cov.:
32
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.:
0
Cov.:
32
AF XY:
0.000618
AC XY:
46
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.:
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:2Uncertain:3
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Pathogenic:1Uncertain:1
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 29, 2025This 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. -
Uncertain significance, criteria provided, single submitterclinical testingGeneDxNov 06, 2024Observed 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) -
Autosomal recessive nonsyndromic hearing loss 93 Pathogenic:1Uncertain:1
Likely pathogenic, no assertion criteria providedresearchInstitute of Human Genetics, University of UlmFeb 13, 2020- -
Uncertain significance, criteria provided, single submitterclinical testingDaryl Scott Lab, Baylor College of MedicineNov 10, 2023- -
not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineSep 13, 2018The 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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs145369252; hg19: chr11-67287311; API