rs764149433

Positions:

• chr3-122261548-C-A
• chr3-122261548-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate

The NM_000388.4(CASR):​c.513C>A​(p.Ser171Arg) 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 1,461,854 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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. S171N) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CASR NM_000388.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 0.573

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 9 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.922

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CASR	NM_000388.4	c.513C>A	p.Ser171Arg	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.513C>A	p.Ser171Arg	missense_variant	4/7	1	NM_000388.4	ENSP00000491584.2
CASR	ENST00000498619.4	c.513C>A	p.Ser171Arg	missense_variant	4/7	1		ENSP00000420194.1
CASR	ENST00000638421.1	c.513C>A	p.Ser171Arg	missense_variant	4/7	5		ENSP00000492190.1
CASR	ENST00000490131.7	c.513C>A	p.Ser171Arg	missense_variant	3/5	5		ENSP00000418685.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461854 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727234

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Molecular Diagnostics Lab, Nemours Children's Health, Delaware

Dec 30, 2015

- -

Nephrolithiasis/nephrocalcinosis Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 26, 2023

The p.S171R variant (also known as c.513C>A), located in coding exon 3 of the CASR gene, results from a C to A substitution at nucleotide position 513. The serine at codon 171 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been identified in multiple individuals diagnosed with familial hypocalciuric hypercalcemia (FHH) (Vargas-Poussou R et al. J Clin Endocrinol Metab, 2016 May;101:2185-95; Khairi S et al. Horm Cancer, 2020 Oct;11:250-255). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 17, 2023

This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 171 of the CASR protein (p.Ser171Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with familial hypocalciuric hypercalcemia (PMID: 26963950). ClinVar contains an entry for this variant (Variation ID: 410349). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	D;D;.;.
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.94	.;D;D;D
M_CAP	Pathogenic	0.29	D
MetaRNN	Pathogenic	0.92	D;D;D;D
MetaSVM	Uncertain	0.77	D
MutationAssessor	Pathogenic	3.6	H;H;H;.
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-2.7	.;.;D;D
REVEL	Pathogenic	0.80
Sift	Uncertain	0.020	.;.;D;D
Sift4G	Uncertain	0.013	.;.;D;D
Polyphen		1.0	D;D;.;.
Vest4		0.95, 0.94
MutPred		0.81		Gain of MoRF binding (P = 0.0219);Gain of MoRF binding (P = 0.0219);Gain of MoRF binding (P = 0.0219);Gain of MoRF binding (P = 0.0219);
MVP		0.98
MPC		1.7
ClinPred		0.99	D
GERP RS		3.8
Varity_R		0.96
gMVP		0.99

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: rs764149433; hg19: chr3-121980395;