rs139417576
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 3P and 6B. PM1PP2BP4BP6BS1
The NM_000388.4(CASR):c.2237C>T(p.Ala746Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000279 in 1,613,934 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A746T) has been classified as Uncertain significance.
Frequency
Consequence
NM_000388.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CASR | NM_000388.4 | c.2237C>T | p.Ala746Val | missense_variant | 7/7 | ENST00000639785.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CASR | ENST00000639785.2 | c.2237C>T | p.Ala746Val | missense_variant | 7/7 | 1 | NM_000388.4 | P1 | |
CASR | ENST00000498619.4 | c.2267C>T | p.Ala756Val | missense_variant | 7/7 | 1 | |||
CASR | ENST00000638421.1 | c.2237C>T | p.Ala746Val | missense_variant | 7/7 | 5 | P1 | ||
CASR | ENST00000490131.7 | c.2006C>T | p.Ala669Val | missense_variant | 5/5 | 5 |
Frequencies
GnomAD3 genomes AF: 0.000191 AC: 29AN: 152174Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000280 AC: 7AN: 250410Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135556
GnomAD4 exome AF: 0.0000109 AC: 16AN: 1461642Hom.: 0 Cov.: 33 AF XY: 0.00000688 AC XY: 5AN XY: 727140
GnomAD4 genome AF: 0.000190 AC: 29AN: 152292Hom.: 0 Cov.: 32 AF XY: 0.000188 AC XY: 14AN XY: 74470
ClinVar
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 22, 2023 | Variant summary: CASR c.2237C>T (p.Ala746Val) results in a non-conservative amino acid change located in the GPCR family 3, C-terminal domain (IPR017978) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.3e-05 in 281788 control chromosomes. The observed variant frequency is approximately 3.41 fold of the estimated maximal expected allele frequency for a pathogenic variant in CASR causing Familial Hypocalciuric Hypercalcemia phenotype (1.3e-05), suggesting that the variant is benign. c.2237C>T has been reported in the literature in at-least two individuals affected with Familial Hypocalciuric Hypercalcemia (example, Vargas-Poussou_2016, Hureaux_2019). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 31189130, 31672324, 26963950, 34088669). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. One submitter classified the variant as likely benign, and one submitter classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. - |
Autosomal dominant hypocalcemia 1;C1809471:Familial hypocalciuric hypercalcemia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 01, 2023 | This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 746 of the CASR protein (p.Ala746Val). This variant is present in population databases (rs139417576, gnomAD 0.05%). This missense change has been observed in individual(s) with familial hypocalciuric hypercalcemia (PMID: 26963950, 31672324). ClinVar contains an entry for this variant (Variation ID: 463921). 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 tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Nephrolithiasis/nephrocalcinosis Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 23, 2023 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at