3-122261950-C-G

Position:

• chr3-122261950-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_000388.4(CASR):​c.915C>G​(p.Ile305Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,804 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CASR NM_000388.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.38

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 3 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CASR	NM_000388.4	c.915C>G	p.Ile305Met	missense_variant	4/7	ENST00000639785.2	NP_000379.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CASR	ENST00000639785.2	c.915C>G	p.Ile305Met	missense_variant	4/7	1	NM_000388.4	ENSP00000491584.2
CASR	ENST00000498619.4	c.915C>G	p.Ile305Met	missense_variant	4/7	1		ENSP00000420194.1
CASR	ENST00000638421.1	c.915C>G	p.Ile305Met	missense_variant	4/7	5		ENSP00000492190.1
CASR	ENST00000490131.7	c.915C>G	p.Ile305Met	missense_variant	3/5	5		ENSP00000418685.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461804 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 727184

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	0.0
CADD	Benign	5.3
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.44	T;T;.;.
Eigen	Benign	0.037
Eigen_PC	Benign	-0.11
FATHMM_MKL	Benign	0.24	N
LIST_S2	Uncertain	0.93	.;D;D;D
M_CAP	Benign	0.061	D
MetaRNN	Uncertain	0.62	D;D;D;D
MetaSVM	Uncertain	0.097	D
MutationAssessor	Uncertain	2.3	M;M;M;.
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-1.6	.;.;N;N
REVEL	Uncertain	0.58
Sift	Uncertain	0.0060	.;.;D;D
Sift4G	Uncertain	0.057	.;.;T;T
Polyphen		1.0	D;D;.;.
Vest4		0.53, 0.57
MutPred		0.61		Gain of disorder (P = 0.0436);Gain of disorder (P = 0.0436);Gain of disorder (P = 0.0436);Gain of disorder (P = 0.0436);
MVP		0.91
MPC		1.6
ClinPred		0.82	D
GERP RS		-1.1
Varity_R		0.84
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

LitVar

Other links and lift over

dbSNP: rs200528343; hg19: chr3-121980797; COSMIC: COSV105893307; COSMIC: COSV105893307;