rs121909261

Positions:

• chr3-122283997-G-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5

The ENST00000639785.2(CASR):​c.2043G>T​(p.Gln681His) variant causes a missense change involving the alteration of a non-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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q681R) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CASR ENST00000639785.2 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 3.00

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 Pathogenic. Variant got 10 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 12 uncertain in ENST00000639785.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-122283996-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1256480.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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, 0.925
• PP5: Variant 3-122283997-G-T is Pathogenic according to our data. Variant chr3-122283997-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 8320.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr3-122283997-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CASR	NM_000388.4	c.2043G>T	p.Gln681His	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.2043G>T	p.Gln681His	missense_variant	7/7	1	NM_000388.4	ENSP00000491584	P1
CASR	ENST00000498619.4	c.2073G>T	p.Gln691His	missense_variant	7/7	1		ENSP00000420194
CASR	ENST00000638421.1	c.2043G>T	p.Gln681His	missense_variant	7/7	5		ENSP00000492190	P1
CASR	ENST00000490131.7	c.1812G>T	p.Gln604His	missense_variant	5/5	5		ENSP00000418685

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Alfa AF: 0.00153 Hom.: 0

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

May 01, 1996

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Benign	17
DANN	Benign	0.95
DEOGEN2	Benign	0.42	T;T;.;.
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.15
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.93	.;D;D;D
M_CAP	Benign	0.084	D
MetaRNN	Pathogenic	0.93	D;D;D;D
MetaSVM	Uncertain	-0.083	T
MutationAssessor	Benign	1.6	L;L;.;.
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	0.99	.;.;N;.
REVEL	Uncertain	0.62
Sift	Benign	0.60	.;.;T;.
Sift4G	Benign	0.83	.;.;T;.
Polyphen		1.0	D;D;.;.
Vest4		0.97
MutPred		0.91		.;.;Gain of sheet (P = 0.0827);.;
MVP		0.95
MPC		1.5
ClinPred		0.51	D
GERP RS		3.3
Varity_R		0.25
gMVP		0.93

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: rs121909261; hg19: chr3-122002844;