3-122254320-T-C

Variant names:

• chr3-122254320-T-C
• NM_000388.4:c.131T>C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP2

The NM_000388.4(CASR):​c.131T>C​(p.Val44Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: 7.95

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.

• PM1: In a region_of_interest Ligand-binding 1 (LB1) (size 166) in uniprot entity CASR_HUMAN there are 70 pathogenic changes around while only 0 benign (100%) in NM_000388.4
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASR	NM_000388.4	c.131T>C	p.Val44Ala	missense_variant	Exon 2 of 7	ENST00000639785.2	NP_000379.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CASR	ENST00000639785.2	c.131T>C	p.Val44Ala	missense_variant	Exon 2 of 7	1	NM_000388.4	ENSP00000491584.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	T;T;.;.
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.84	.;T;T;T
M_CAP	Uncertain	0.094	D
MetaRNN	Uncertain	0.54	D;D;D;D
MetaSVM	Uncertain	0.059	D
MutationAssessor	Benign	1.8	L;L;L;.
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.50	.;.;N;N
REVEL	Uncertain	0.51
Sift	Benign	0.20	.;.;T;T
Sift4G	Benign	0.85	.;.;T;T
Polyphen		0.82	P;P;.;.
Vest4		0.53, 0.54
MutPred		0.41		Gain of disorder (P = 0.047);Gain of disorder (P = 0.047);Gain of disorder (P = 0.047);Gain of disorder (P = 0.047);
MVP		0.99
MPC		1.1
ClinPred		0.89	D
GERP RS		5.4
Varity_R		0.32
gMVP		0.79

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-121973167;