rs775751453

Positions:

• chr3-122261648-C-G
• chr3-122261648-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_000388.4(CASR):​c.613C>G​(p.Arg205Gly) 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 benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R205C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CASR NM_000388.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.59

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 Uncertain_significance. Variant got 1 ACMG points.

• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.24232039).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CASR	NM_000388.4	c.613C>G	p.Arg205Gly	missense_variant	4/7	ENST00000639785.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CASR	ENST00000639785.2	c.613C>G	p.Arg205Gly	missense_variant	4/7	1	NM_000388.4	P1
CASR	ENST00000498619.4	c.613C>G	p.Arg205Gly	missense_variant	4/7	1
CASR	ENST00000638421.1	c.613C>G	p.Arg205Gly	missense_variant	4/7	5		P1
CASR	ENST00000490131.7	c.613C>G	p.Arg205Gly	missense_variant	3/5	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Nephrolithiasis/nephrocalcinosis Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 28, 2022

The p.R205G variant (also known as c.613C>G), located in coding exon 3 of the CASR gene, results from a C to G substitution at nucleotide position 613. The arginine at codon 205 is replaced by glycine, an amino acid with dissimilar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Autosomal dominant hypocalcemia 1;C1809471:Familial hypocalciuric hypercalcemia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 13, 2019

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15"). This variant has not been reported in the literature in individuals with CASR-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with glycine at codon 205 of the CASR protein (p.Arg205Gly). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and glycine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.091	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	14
DANN	Benign	0.66
DEOGEN2	Benign	0.32	T;T;.;.
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.12
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.89	.;D;D;D
M_CAP	Benign	0.061	D
MetaRNN	Benign	0.24	T;T;T;T
MetaSVM	Benign	-0.58	T
MutationAssessor	Benign	-1.5	N;N;N;.
MutationTaster	Benign	0.91	D;D;D
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	3.5	.;.;N;N
REVEL	Uncertain	0.40
Sift	Benign	1.0	.;.;T;T
Sift4G	Benign	1.0	.;.;T;T
Polyphen		0.0060	B;B;.;.
Vest4		0.36, 0.36
MutPred		0.59		Loss of stability (P = 0.0487);Loss of stability (P = 0.0487);Loss of stability (P = 0.0487);Loss of stability (P = 0.0487);
MVP		0.76
MPC		0.79
ClinPred		0.38	T
GERP RS		5.2
Varity_R		0.71
gMVP		0.53

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: rs775751453; hg19: chr3-121980495;