rs104893717

Variant names:

• chr3-122254227-T-C
• rs104893717
• NM_000388.4:c.38T>C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP2 PP3_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
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• 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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the CASR gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 114 curated pathogenic missense variants (we use a threshold of 10). The gene has 10 curated benign missense variants. Gene score misZ: 3.1237 (above the threshold of 3.09). Trascript score misZ: 4.8257 (above the threshold of 3.09). GenCC associations: The gene is linked to epilepsy, autosomal dominant hypocalcemia, familial hypocalciuric hypercalcemia 1, epilepsy, idiopathic generalized, susceptibility to, 8, neonatal severe primary hyperparathyroidism, autosomal dominant hypocalcemia 1.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.948

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASR	NM_000388.4	c.38T>C	p.Leu13Pro	missense_variant	Exon 2 of 7	ENST00000639785.2	NP_000379.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CASR	ENST00000639785.2	c.38T>C	p.Leu13Pro	missense_variant	Exon 2 of 7	1	NM_000388.4	ENSP00000491584.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Familial hypocalciuric hypercalcemia 1 Pathogenic:1

Jun 15, 2005

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Nephrolithiasis/nephrocalcinosis Uncertain:1

Jan 25, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Benign	18
DANN	Uncertain	0.97
DEOGEN2	Benign	0.38	T;T;.;.
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.34
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.66	.;T;T;T
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.95	D;D;D;D
MetaSVM	Uncertain	-0.043	T
MutationAssessor	Benign	1.2	L;L;L;.
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.68	.;.;N;N
REVEL	Uncertain	0.56
Sift	Uncertain	0.014	.;.;D;D
Sift4G	Benign	0.076	.;.;T;T
Polyphen		0.30	B;B;.;.
Vest4		0.85, 0.83
MutPred		0.73		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		0.38	T
GERP RS		4.1
Varity_R		0.50
gMVP		0.83

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs104893717; hg19: chr3-121973074;