rs562364178
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM1PP2
The NM_000388.4(CASR):c.2236G>A(p.Ala746Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,613,856 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. A746V) has been classified as Likely benign.
Frequency
Consequence
NM_000388.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CASR | NM_000388.4 | c.2236G>A | p.Ala746Thr | missense_variant | 7/7 | ENST00000639785.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CASR | ENST00000639785.2 | c.2236G>A | p.Ala746Thr | missense_variant | 7/7 | 1 | NM_000388.4 | P1 | |
CASR | ENST00000498619.4 | c.2266G>A | p.Ala756Thr | missense_variant | 7/7 | 1 | |||
CASR | ENST00000638421.1 | c.2236G>A | p.Ala746Thr | missense_variant | 7/7 | 5 | P1 | ||
CASR | ENST00000490131.7 | c.2005G>A | p.Ala669Thr | missense_variant | 5/5 | 5 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152118Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000799 AC: 2AN: 250354Hom.: 0 AF XY: 0.00000738 AC XY: 1AN XY: 135526
GnomAD4 exome AF: 0.00000547 AC: 8AN: 1461620Hom.: 0 Cov.: 33 AF XY: 0.00000688 AC XY: 5AN XY: 727120
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152236Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74424
ClinVar
Submissions by phenotype
Nephrolithiasis/nephrocalcinosis Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 23, 2020 | The p.A746T variant (also known as c.2236G>A), located in coding exon 6 of the CASR gene, results from a G to A substitution at nucleotide position 2236. The alanine at codon 746 is replaced by threonine, an amino acid with similar properties. An alternate amino acid substitution at this codon, p.A746V, was described in a familial hypercalciuric hypercalcemia cohort; however, clinical details were limited (Vargas-Poussou R et al. J. Clin. Endocrinol. Metab., 2016 05;101:2185-95). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Autosomal dominant hypocalcemia 1;C1809471:Familial hypocalciuric hypercalcemia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 10, 2023 | This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 746 of the CASR protein (p.Ala746Thr). This variant is present in population databases (rs562364178, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with CASR-related conditions. ClinVar contains an entry for this variant (Variation ID: 410321). 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. 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at