rs373376842
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PP2BP4_Moderate
The NM_000388.4(CASR):c.712G>A(p.Asp238Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000118 in 1,614,060 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_000388.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CASR | ENST00000639785.2 | c.712G>A | p.Asp238Asn | missense_variant | Exon 4 of 7 | 1 | NM_000388.4 | ENSP00000491584.2 | ||
CASR | ENST00000498619.4 | c.712G>A | p.Asp238Asn | missense_variant | Exon 4 of 7 | 1 | ENSP00000420194.1 | |||
CASR | ENST00000638421.1 | c.712G>A | p.Asp238Asn | missense_variant | Exon 4 of 7 | 5 | ENSP00000492190.1 | |||
CASR | ENST00000490131.7 | c.712G>A | p.Asp238Asn | missense_variant | Exon 3 of 5 | 5 | ENSP00000418685.2 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152204Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251192Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135734
GnomAD4 exome AF: 0.0000109 AC: 16AN: 1461856Hom.: 0 Cov.: 34 AF XY: 0.00000825 AC XY: 6AN XY: 727226
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152204Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74364
ClinVar
Submissions by phenotype
Nephrolithiasis/nephrocalcinosis Uncertain:1
The p.D238N variant (also known as c.712G>A), located in coding exon 3 of the CASR gene, results from a G to A substitution at nucleotide position 712. The aspartic acid at codon 238 is replaced by asparagine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -
CASR-related disorder Uncertain:1
The CASR c.712G>A variant is predicted to result in the amino acid substitution p.Asp238Asn. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0058% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/3-121980594-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Autosomal dominant hypocalcemia 1;C1809471:Familial hypocalciuric hypercalcemia Uncertain:1
This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 238 of the CASR protein (p.Asp238Asn). This variant is present in population databases (rs373376842, gnomAD 0.006%). 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: 963952). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The asparagine 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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at