rs104893690

chr3-122283699-G-Achr3-122283699-G-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Moderate

The NM_000388.4(CASR):c.1745G>A(p.Cys582Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,692 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/20 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C582F) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CASR NM_000388.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 10.0

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 Pathogenic. Variant got 13 ACMG points.

• PM1: In a disulfide_bond (size 14) in uniprot entity CASR_HUMAN there are 9 pathogenic changes around while only 0 benign (100%) 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 chr3-122283698-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 853442.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant where missense usually causes diseases, CASR
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.986
• PP5: Variant 3-122283699-G-A is Pathogenic according to our data. Variant chr3-122283699-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 8318.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-122283699-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CASR	NM_000388.4	c.1745G>A	p.Cys582Tyr	missense_variant	7/7	ENST00000639785.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CASR	ENST00000639785.2	c.1745G>A	p.Cys582Tyr	missense_variant	7/7	1	NM_000388.4	P1
CASR	ENST00000498619.4	c.1775G>A	p.Cys592Tyr	missense_variant	7/7	1
CASR	ENST00000638421.1	c.1745G>A	p.Cys582Tyr	missense_variant	7/7	5		P1
CASR	ENST00000490131.7	c.1514G>A	p.Cys505Tyr	missense_variant	5/5	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461692 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727166

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Neonatal severe primary hyperparathyroidism Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 01, 1995

- -

Autosomal dominant hypocalcemia 1;C1809471:Familial hypocalciuric hypercalcemia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 28, 2019

This variant disrupts the p.Cys582 amino acid residue in CASR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17698911, 23764372). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. This variant has been observed in a family and in individuals affected with familial hypocalciuric hypercalcemia (PMID: 17698911, 22192860, 23764372) and in two individuals affected with early onset hyperparathyroidism (PMID: 18219222, 8675635). ClinVar contains an entry for this variant (Variation ID: 8318). This variant is not present in population databases (rs104893690, ExAC no frequency). This sequence change replaces cysteine with tyrosine at codon 582 of the CASR protein (p.Cys582Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine. For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CASR protein function. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
Cadd	Pathogenic	30
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D;D;.;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	1.0	D
M_CAP	Pathogenic	0.75	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.8	H;H;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.85	D
Polyphen		1.0	D;D;.;.
Vest4		0.99
MutPred		0.83		.;.;Gain of glycosylation at T587 (P = 0.0286);.;
MVP		0.99
MPC		2.1
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.99
gMVP		1.0

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: rs104893690; hg19: chr3-122002546;