rs762998933
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM1PP2BP4
The NM_000388.4(CASR):c.566A>G(p.Asn189Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000316 in 1,614,094 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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. N189I) has been classified as Uncertain significance.
Frequency
Consequence
NM_000388.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CASR | NM_000388.4 | c.566A>G | p.Asn189Ser | missense_variant | 4/7 | ENST00000639785.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CASR | ENST00000639785.2 | c.566A>G | p.Asn189Ser | missense_variant | 4/7 | 1 | NM_000388.4 | P1 | |
CASR | ENST00000498619.4 | c.566A>G | p.Asn189Ser | missense_variant | 4/7 | 1 | |||
CASR | ENST00000638421.1 | c.566A>G | p.Asn189Ser | missense_variant | 4/7 | 5 | P1 | ||
CASR | ENST00000490131.7 | c.566A>G | p.Asn189Ser | missense_variant | 3/5 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152232Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251222Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135762
GnomAD4 exome AF: 0.0000322 AC: 47AN: 1461862Hom.: 0 Cov.: 33 AF XY: 0.0000330 AC XY: 24AN XY: 727234
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152232Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74366
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 | Mar 07, 2023 | Variant summary: CASR c.566A>G (p.Asn189Ser) results in a conservative amino acid change located in the Receptor, ligand binding region (IPR001828) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251222 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.566A>G has been reported in the literature as a VUS in settings of multigene panel testing at-least one individual reportedly affected with Familial Benign Hypercalcemia (example, Hureaux_2019). This report does not provide unequivocal conclusions about association of the variant with Familial Hypocalciuric Hypercalcemia. Three ClinVar submitters have assessed the variant since 2014: all three classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Hypercalcemia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genetics and Molecular Pathology, SA Pathology | Aug 04, 2020 | - - |
Autosomal dominant hypocalcemia 1;C1809471:Familial hypocalciuric hypercalcemia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 17, 2023 | This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 189 of the CASR protein (p.Asn189Ser). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with clinical features of familial hypocalciuric hypercalcemia (PMID: 31672324). ClinVar contains an entry for this variant (Variation ID: 419926). 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. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Oct 21, 2016 | A variant of uncertain significance has been identified in the CASR gene. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. N189S is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where amino acids with similar properties to Asparagine are tolerated across species. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function, and a study by Stewart et al. found no detectable difference in activity from wild type when N189S is assessed in a calcium-dependent MAP kinase activation model (Stewart et al., 2004). Missense variants in nearby residues (R185Q, D190G/E, D191K) have been reported in the Human Gene Mutation Database in association with CASR-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at