rs1553768892

Positions:

• chr3-122283719-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP2

The NM_000388.4(CASR):​c.1765T>G​(p.Phe589Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F589L) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CASR NM_000388.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.02

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a region_of_interest Cysteine-rich (CR) (size 70) in uniprot entity CASR_HUMAN there are 23 pathogenic changes around while only 1 benign (96%) in NM_000388.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-122283719-T-C is described in Lovd as [Pathogenic].
• 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.1765T>G	p.Phe589Val	missense_variant	7/7	ENST00000639785.2	NP_000379.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CASR	ENST00000639785.2	c.1765T>G	p.Phe589Val	missense_variant	7/7	1	NM_000388.4	ENSP00000491584	P1
CASR	ENST00000498619.4	c.1795T>G	p.Phe599Val	missense_variant	7/7	1		ENSP00000420194
CASR	ENST00000638421.1	c.1765T>G	p.Phe589Val	missense_variant	7/7	5		ENSP00000492190	P1
CASR	ENST00000490131.7	c.1534T>G	p.Phe512Val	missense_variant	5/5	5		ENSP00000418685

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Athena Diagnostics

Oct 25, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.84	D;D;.;.
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	.;D;D;D
M_CAP	Uncertain	0.094	D
MetaRNN	Uncertain	0.72	D;D;D;D
MetaSVM	Uncertain	0.17	D
MutationAssessor	Uncertain	2.7	M;M;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.50	T
PROVEAN	Pathogenic	-5.0	.;.;D;.
REVEL	Uncertain	0.49
Sift	Benign	0.031	.;.;D;.
Sift4G	Benign	0.13	.;.;T;.
Polyphen		0.081	B;B;.;.
Vest4		0.30
MutPred		0.55		.;.;Gain of catalytic residue at F599 (P = 0.0329);.;
MVP		0.90
MPC		1.1
ClinPred		0.98	D
GERP RS		5.9
Varity_R		0.77
gMVP		0.90

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: rs1553768892; hg19: chr3-122002566;