3-122254200-A-G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PP2 BP4_Moderate

The NM_000388.4(CASR):c.11A>G(p.Tyr4Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,460,742 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign 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. Y4H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: CASR NM_000388.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 0.736

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_benign. Variant got -1 ACMG points.

• PP2: Missense variant where missense usually causes diseases, CASR
• BP4: Computational evidence support a benign effect (MetaRNN=0.1515572).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CASR	NM_000388.4	c.11A>G	p.Tyr4Cys	missense_variant	2/7	ENST00000639785.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CASR	ENST00000639785.2	c.11A>G	p.Tyr4Cys	missense_variant	2/7	1	NM_000388.4	P1
CASR	ENST00000498619.4	c.11A>G	p.Tyr4Cys	missense_variant	2/7	1
CASR	ENST00000638421.1	c.11A>G	p.Tyr4Cys	missense_variant	2/7	5		P1
CASR	ENST00000490131.7	c.11A>G	p.Tyr4Cys	missense_variant	1/5	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1460742 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 726662

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

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

Nephrolithiasis/nephrocalcinosis Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 28, 2023

The p.Y4C variant (also known as c.11A>G), located in coding exon 1 of the CASR gene, results from an A to G substitution at nucleotide position 11. The tyrosine at codon 4 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Familial hypocalciuric hypercalcemia 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 31, 2022

This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 4 of the CASR protein (p.Tyr4Cys). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CASR-related conditions. ClinVar contains an entry for this variant (Variation ID: 567686). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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	Benign	0.060
BayesDel_addAF	Uncertain	0.057	T
BayesDel_noAF	Benign	-0.16
Cadd	Benign	19
Dann	Uncertain	0.98
DEOGEN2	Benign	0.32	T;T;.;.
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.22	N
M_CAP	Benign	0.070	D
MetaRNN	Benign	0.15	T;T;T;T
MetaSVM	Benign	-0.41	T
MutationAssessor	Benign	1.4	L;L;L;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.31	T
Polyphen		0.26	B;B;.;.
Vest4		0.40, 0.36
MutPred		0.45		Loss of glycosylation at S5 (P = 0.0332);Loss of glycosylation at S5 (P = 0.0332);Loss of glycosylation at S5 (P = 0.0332);Loss of glycosylation at S5 (P = 0.0332);
MVP		0.95
MPC		0.75
ClinPred		0.13	T
GERP RS		1.1
Varity_R		0.080
gMVP		0.75

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: rs1171102282; hg19: chr3-121973047;