rs104893718

Positions:

• chr3-122284134-T-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP2 PP3_Moderate PP5

The NM_000388.4(CASR):​c.2180T>A​(p.Leu727Gln) 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 Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CASR NM_000388.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.98

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 8 ACMG points.

• PM1: In a transmembrane_region Helical; Name=4 (size 20) in uniprot entity CASR_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) in NM_000388.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CASR. . Gene score misZ 3.1237 (greater than the threshold 3.09). Trascript score misZ 4.8257 (greater than threshold 3.09). GenCC has associacion of gene with 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, 0.889
• PP5: Variant 3-122284134-T-A is Pathogenic according to our data. Variant chr3-122284134-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 8354.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr3-122284134-T-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CASR	NM_000388.4	c.2180T>A	p.Leu727Gln	missense_variant	7/7	ENST00000639785.2	NP_000379.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CASR	ENST00000639785.2	c.2180T>A	p.Leu727Gln	missense_variant	7/7	1	NM_000388.4	ENSP00000491584	P1
CASR	ENST00000498619.4	c.2210T>A	p.Leu737Gln	missense_variant	7/7	1		ENSP00000420194
CASR	ENST00000638421.1	c.2180T>A	p.Leu727Gln	missense_variant	7/7	5		ENSP00000492190	P1
CASR	ENST00000490131.7	c.1949T>A	p.Leu650Gln	missense_variant	5/5	5		ENSP00000418685

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Autosomal dominant hypocalcemia 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 01, 2006

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.75	D;D;.;.
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.96	.;D;D;D
M_CAP	Pathogenic	0.39	D
MetaRNN	Pathogenic	0.89	D;D;D;D
MetaSVM	Uncertain	0.76	D
MutationAssessor	Uncertain	2.5	M;M;.;.
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-2.6	.;.;D;D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0030	.;.;D;D
Sift4G	Uncertain	0.059	.;.;T;.
Polyphen		1.0	D;D;.;.
Vest4		0.97
MutPred		0.68		.;.;Gain of catalytic residue at L737 (P = 0.0191);.;
MVP		0.99
MPC		1.6
ClinPred		0.99	D
GERP RS		6.0
Varity_R		0.76
gMVP		0.91

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: rs104893718; hg19: chr3-122002981;