chr3-122275878-T-A

Position:

• chr3-122275878-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM1 PP2 BP4_Moderate

The NM_000388.4(CASR):​c.1444T>A​(p.Cys482Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000547 in 1,461,826 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: CASR NM_000388.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.98

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 1 ACMG points.

• PM1: In a site Important for ability of agonist AMG 416 to activate G-protein-coupled receptor activity (size 0) in uniprot entity CASR_HUMAN
• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.19921407).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CASR	NM_000388.4	c.1444T>A	p.Cys482Ser	missense_variant	5/7	ENST00000639785.2	NP_000379.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CASR	ENST00000639785.2	c.1444T>A	p.Cys482Ser	missense_variant	5/7	1	NM_000388.4	ENSP00000491584	P1
CASR	ENST00000498619.4	c.1444T>A	p.Cys482Ser	missense_variant	5/7	1		ENSP00000420194
CASR	ENST00000638421.1	c.1444T>A	p.Cys482Ser	missense_variant	5/7	5		ENSP00000492190	P1
CASR	ENST00000490131.7	c.1378-6235T>A		intron_variant		5		ENSP00000418685

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000795 AC: 2 AN: 251452 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135892

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461826 Hom.: 0 Cov.: 32 AF XY: 0.00000963 AC XY: 7 AN XY: 727216

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: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 29, 2019

In summary, this variant is a rare missense change that does not appear to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies have shown that this missense change does not affect cell surface expression or receptor dimerization in vitro (PMID: 10488104). This variant is present in population databases (rs774174934, ExAC 0.006%) but has not been reported in the literature in individuals with a CASR-related disease. This sequence change replaces cysteine with serine at codon 482 of the CASR protein (p.Cys482Ser). The cysteine residue is moderately conserved and there is a moderate physicochemical difference between cysteine and serine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	20
DANN	Benign	0.90
DEOGEN2	Benign	0.32	T;T;.
Eigen	Benign	-0.31
Eigen_PC	Benign	0.0059
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.64	.;T;T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.20	T;T;T
MetaSVM	Benign	-0.62	T
MutationAssessor	Benign	-2.1	N;N;N
MutationTaster	Benign	0.79	D;D;D
PrimateAI	Benign	0.42	T
PROVEAN	Benign	2.6	.;.;N
REVEL	Benign	0.24
Sift	Benign	0.14	.;.;T
Sift4G	Benign	0.27	.;.;T
Polyphen		0.0	B;B;.
Vest4		0.27
MutPred		0.46		Gain of disorder (P = 6e-04);Gain of disorder (P = 6e-04);Gain of disorder (P = 6e-04);
MVP		0.86
MPC		0.74
ClinPred		0.26	T
GERP RS		5.7
Varity_R		0.23
gMVP		0.45

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: rs774174934; hg19: chr3-121994725;