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):āc.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
Consequence
NM_016366.3 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000664 AC: 101AN: 152114Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000314 AC: 79AN: 251258Hom.: 0 AF XY: 0.000383 AC XY: 52AN XY: 135822
GnomAD4 exome AF: 0.000348 AC: 508AN: 1461752Hom.: 1 Cov.: 32 AF XY: 0.000362 AC XY: 263AN XY: 727172
GnomAD4 genome AF: 0.000663 AC: 101AN: 152232Hom.: 0 Cov.: 32 AF XY: 0.000618 AC XY: 46AN XY: 74432
ClinVar
Submissions by phenotype
not provided Pathogenic:1Uncertain:1
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) -
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:1Uncertain:1
- -
- -
not specified Uncertain:1
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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at