3-122261995-C-G

Variant names:

• chr3-122261995-C-G
• rs753011255
• NM_000388.4:c.960C>G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 PP3_Moderate

The NM_000388.4(CASR):​c.960C>G​(p.Phe320Leu) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CASR NM_000388.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.154

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 5 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.867

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASR	NM_000388.4	c.960C>G	p.Phe320Leu	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.960C>G	p.Phe320Leu	missense_variant	Exon 4 of 7	1	NM_000388.4	ENSP00000491584.2
CASR	ENST00000498619.4	c.960C>G	p.Phe320Leu	missense_variant	Exon 4 of 7	1		ENSP00000420194.1
CASR	ENST00000638421.1	c.960C>G	p.Phe320Leu	missense_variant	Exon 4 of 7	5		ENSP00000492190.1
CASR	ENST00000490131.7	c.960C>G	p.Phe320Leu	missense_variant	Exon 3 of 5	5		ENSP00000418685.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Benign	0.57
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.75	D;D;.;.
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.64
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.92	.;D;D;D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.87	D;D;D;D
MetaSVM	Uncertain	0.00020	D
MutationAssessor	Benign	1.5	L;L;L;.
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-2.9	.;.;D;D
REVEL	Uncertain	0.62
Sift	Uncertain	0.013	.;.;D;D
Sift4G	Benign	0.17	.;.;T;T
Polyphen		1.0	D;D;.;.
Vest4		0.89, 0.89
MutPred		0.74		Loss of glycosylation at T317 (P = 0.0544);Loss of glycosylation at T317 (P = 0.0544);Loss of glycosylation at T317 (P = 0.0544);Loss of glycosylation at T317 (P = 0.0544);
MVP		0.83
MPC		1.5
ClinPred		0.98	D
GERP RS		-6.8
Varity_R		0.73
gMVP		0.89

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: rs753011255; hg19: chr3-121980842;