rs104893717
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP2PP3_Strong
The NM_000388.4(CASR):c.38T>C(p.Leu13Pro) variant causes a missense change. 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 Uncertain significance (★).
Frequency
Genomes: not found (cov: 32)
Consequence
CASR
NM_000388.4 missense
NM_000388.4 missense
Scores
3
4
7
Clinical Significance
Conservation
PhyloP100: 3.71
Genes affected
CASR (HGNC:1514): (calcium sensing receptor) The protein encoded by this gene is a plasma membrane G protein-coupled receptor that senses small changes in circulating calcium concentration. The encoded protein couples this information to intracellular signaling pathways that modify parathyroid hormone secretion or renal cation handling, and thus this protein plays an essential role in maintaining mineral ion homeostasis. Mutations in this gene are a cause of familial hypocalciuric hypercalcemia, neonatal severe hyperparathyroidism, and autosomal dominant hypocalcemia. [provided by RefSeq, Aug 2017]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP2
?
Missense variant where missense usually causes diseases, CASR
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.948
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CASR | NM_000388.4 | c.38T>C | p.Leu13Pro | missense_variant | 2/7 | ENST00000639785.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CASR | ENST00000639785.2 | c.38T>C | p.Leu13Pro | missense_variant | 2/7 | 1 | NM_000388.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Uncertain significance
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Familial hypocalciuric hypercalcemia 1 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 15, 2005 | - - |
Nephrolithiasis/nephrocalcinosis Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 25, 2022 | The p.L13P variant (also known as c.38T>C), located in coding exon 1 of the CASR gene, results from a T to C substitution at nucleotide position 38. The leucine at codon 13 is replaced by proline, an amino acid with similar properties. This alteration was identified in the homozygous state in a 9 year old Brazilian female with severe hypercalcemia, hypophosphatemia and elevated PTH. The consanguineous parents were heterozygous with mild hypercalcemia (Miyashiro K et al. J Clin Endocrinol Metab, 2004 Dec;89:5936-41). This alteration also showed reduced response to extracellular calcium in three independent studies (Miyashiro K et al. J Clin Endocrinol Metab, 2004 Dec;89:5936-41; Pidasheva S et al. Hum Mol Genet, 2005 Jun;14:1679-90; Lu JY et al. J Pharmacol Exp Ther, 2009 Dec;331:775-86). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Benign
Dann
Uncertain
DEOGEN2
Benign
T;T;.;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Uncertain
T
MutationAssessor
Benign
L;L;L;.
MutationTaster
Benign
A;A;A
PrimateAI
Benign
T
Polyphen
B;B;.;.
Vest4
0.85, 0.83
MutPred
Loss of catalytic residue at L13 (P = 0.0016);Loss of catalytic residue at L13 (P = 0.0016);Loss of catalytic residue at L13 (P = 0.0016);Loss of catalytic residue at L13 (P = 0.0016);
MVP
0.91
MPC
1.1
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at