rs104893698
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP2PP3_ModeratePP5_Moderate
The NM_000388.4(CASR):c.1835T>C(p.Phe612Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. F612F) has been classified as Likely benign.
Frequency
Consequence
NM_000388.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CASR | NM_000388.4 | c.1835T>C | p.Phe612Ser | missense_variant | 7/7 | ENST00000639785.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CASR | ENST00000639785.2 | c.1835T>C | p.Phe612Ser | missense_variant | 7/7 | 1 | NM_000388.4 | P1 | |
CASR | ENST00000498619.4 | c.1865T>C | p.Phe622Ser | missense_variant | 7/7 | 1 | |||
CASR | ENST00000638421.1 | c.1835T>C | p.Phe612Ser | missense_variant | 7/7 | 5 | P1 | ||
CASR | ENST00000490131.7 | c.1604T>C | p.Phe535Ser | missense_variant | 5/5 | 5 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 33
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Autosomal dominant hypocalcemia 1 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 10, 1996 | - - |
Nephrolithiasis/nephrocalcinosis Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 12, 2024 | The c.1835T>C (p.F612S) alteration is located in exon 7 (coding exon 6) of the CASR gene. This alteration results from a T to C substitution at nucleotide position 1835, causing the phenylalanine (F) at amino acid position 612 to be replaced by a serine (S). Based on the available evidence, the CASR c.1835T>C (p.F612S) alteration is classified as likely pathogenic for autosomal dominant CASR-related hypocalcemia; however, it is unlikely to be causative of autosomal recessive neonatal hyperparathyroidism and autosomal dominant hypocalciuric hypercalcemia. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been reported in multiple individuals with clinical features of CASR-related hypocalcemia and cosegregates with disease in two families (Mancilla, 1997; Pearce, 1996). This amino acid position is highly conserved in available vertebrate species. Functional studies indicate this alteration increases sensitivity to extracellular calcium (Mancilla, 1997; Leach, 2012; Hauache, 2000). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at