3-122261786-G-C

Variant names:

• chr3-122261786-G-C
• rs1060502854
• NM_000388.4:c.751G>C

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.751G>C​(p.Glu251Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign 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 U:1
• Conservation: PhyloP100: 4.05

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 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.23643985).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASR	NM_000388.4	c.751G>C	p.Glu251Gln	missense_variant	Exon 4 of 7	ENST00000639785.2	NP_000379.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CASR	ENST00000639785.2	c.751G>C	p.Glu251Gln	missense_variant	Exon 4 of 7	1	NM_000388.4	ENSP00000491584.2
CASR	ENST00000498619.4	c.751G>C	p.Glu251Gln	missense_variant	Exon 4 of 7	1		ENSP00000420194.1
CASR	ENST00000638421.1	c.751G>C	p.Glu251Gln	missense_variant	Exon 4 of 7	5		ENSP00000492190.1
CASR	ENST00000490131.7	c.751G>C	p.Glu251Gln	missense_variant	Exon 3 of 5	5		ENSP00000418685.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Sep 30, 2016

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C25"). This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a CASR-related disease. This sequence change replaces glutamic acid with glutamine at codon 251 of the CASR protein (p.Glu251Gln). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and glutamine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Uncertain	0.047	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.32	T;T;.;.
Eigen	Benign	-0.16
Eigen_PC	Benign	0.054
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.85	.;T;T;T
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.24	T;T;T;T
MetaSVM	Benign	-0.40	T
MutationAssessor	Benign	0.66	N;N;N;.
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.89	.;.;N;N
REVEL	Benign	0.27
Sift	Benign	0.23	.;.;T;T
Sift4G	Benign	0.43	.;.;T;T
Polyphen		0.12	B;B;.;.
Vest4		0.43, 0.46
MutPred		0.43		Gain of glycosylation at S247 (P = 0.0306);Gain of glycosylation at S247 (P = 0.0306);Gain of glycosylation at S247 (P = 0.0306);Gain of glycosylation at S247 (P = 0.0306);
MVP		0.90
MPC		0.60
ClinPred		0.66	D
GERP RS		4.4
Varity_R		0.53
gMVP		0.64

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: rs1060502854; hg19: chr3-121980633;