rs1060502847
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PS1_Very_StrongPM1PM2PP2PP3PP5_Moderate
The ENST00000639785.2(CASR):c.164_165delinsTT(p.Pro55Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P55S) has been classified as Uncertain significance.
Frequency
Consequence
ENST00000639785.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CASR | NM_000388.4 | c.164_165delinsTT | p.Pro55Leu | missense_variant | 2/7 | ENST00000639785.2 | NP_000379.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CASR | ENST00000639785.2 | c.164_165delinsTT | p.Pro55Leu | missense_variant | 2/7 | 1 | NM_000388.4 | ENSP00000491584 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Autosomal dominant hypocalcemia 1;C1809471:Familial hypocalciuric hypercalcemia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Sep 28, 2019 | For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change disrupts CASR protein activity (PMID: 8878438, 19389809, 19759318). While this particular variant has not been described in the literature, a different variant (c.164C>T) giving rise to the same protein effect observed here (p.Pro55Leu) has been reported in several individuals and families affected with familial hypocalciuric hypercalcaemia (PMID: 22422767, 20164288, 11763315, 24947037). The c.164C>T (p.Pro55Leu) variant also segregates with disease in two families (PMID: 8675635, 12580936), indicating that this residue may be critical for protein function. This variant is not present in population databases (ExAC no frequency). This variant is a complex sequence change that replaces a proline with a leucine at codon 55 of the CASR protein (p.Pro55Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at