Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2_SupportingPP2BP4_Moderate
The NM_000388(CASR):c.2956G>A(p.Ala986Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD Genomes project. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A986S) has been classified as Benign.
Verdict is Uncertain_significance. Variant got 2 ACMG points.
GnomAD3 genomesCov.: 33 GnomAD4 exome AF: 0.00000342AC: 5AN: 1461864Hom.: 0 AF XY: 0.00000413AC XY: 3AN XY: 727226
Submissions by phenotype
Autosomal dominant hypocalcemia 1;C1809471:Familial hypocalciuric hypercalcemia
|Uncertain significance, criteria provided, single submitter||clinical testing||Invitae||Aug 31, 2021||This sequence change replaces alanine with threonine at codon 986 of the CASR protein (p.Ala986Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with CASR-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The threonine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -|
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