3-122261747-G-C

Variant names:

• chr3-122261747-G-C
• rs373376842
• NM_000388.4:c.712G>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_000388.4(CASR):​c.712G>C​(p.Asp238His) 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. 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: 4.36

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 2 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=0.35009596).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASR	NM_000388.4	c.712G>C	p.Asp238His	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.712G>C	p.Asp238His	missense_variant	Exon 4 of 7	1	NM_000388.4	ENSP00000491584.2
CASR	ENST00000498619.4	c.712G>C	p.Asp238His	missense_variant	Exon 4 of 7	1		ENSP00000420194.1
CASR	ENST00000638421.1	c.712G>C	p.Asp238His	missense_variant	Exon 4 of 7	5		ENSP00000492190.1
CASR	ENST00000490131.7	c.712G>C	p.Asp238His	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

Mar 10, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with CASR-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces aspartic acid with histidine at codon 238 of the CASR protein (p.Asp238His). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and histidine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Uncertain	0.030	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	23
DANN	Benign	0.89
DEOGEN2	Uncertain	0.43	T;T;.;.
Eigen	Benign	-0.066
Eigen_PC	Benign	0.085
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.90	.;D;D;D
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.35	T;T;T;T
MetaSVM	Benign	-0.36	T
MutationAssessor	Benign	0.86	L;L;L;.
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.72	.;.;N;N
REVEL	Uncertain	0.36
Sift	Benign	0.20	.;.;T;T
Sift4G	Benign	0.13	.;.;T;T
Polyphen		0.0080	B;B;.;.
Vest4		0.26, 0.25
MutPred		0.65		Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);
MVP		0.89
MPC		0.73
ClinPred		0.68	D
GERP RS		5.3
Varity_R		0.45
gMVP		0.77

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: rs373376842; hg19: chr3-121980594;