chr3-122254209-G-A

Position:

• chr3-122254209-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_000388.4(CASR):​c.20G>A​(p.Cys7Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,994 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 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: 0.0000021 (0 hom.)
• Consequence: CASR NM_000388.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.968

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.

• PM2: Very rare variant in population databases, with high coverage
• 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=0.11327803).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CASR	NM_000388.4	c.20G>A	p.Cys7Tyr	missense_variant	2/7	ENST00000639785.2	NP_000379.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CASR	ENST00000639785.2	c.20G>A	p.Cys7Tyr	missense_variant	2/7	1	NM_000388.4	ENSP00000491584.2
CASR	ENST00000498619.4	c.20G>A	p.Cys7Tyr	missense_variant	2/7	1		ENSP00000420194.1
CASR	ENST00000638421.1	c.20G>A	p.Cys7Tyr	missense_variant	2/7	5		ENSP00000492190.1
CASR	ENST00000490131.7	c.20G>A	p.Cys7Tyr	missense_variant	1/5	5		ENSP00000418685.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460994 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726790

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

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

Aug 17, 2023

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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The tyrosine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 851352). This variant has not been reported in the literature in individuals affected with CASR-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 7 of the CASR protein (p.Cys7Tyr). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.058	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	10
DANN	Benign	0.43
DEOGEN2	Benign	0.32	T;T;.;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.84
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.65	.;T;T;T
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.11	T;T;T;T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	-0.74	N;N;N;.
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.28	.;.;N;N
REVEL	Benign	0.23
Sift	Benign	0.57	.;.;T;T
Sift4G	Benign	1.0	.;.;T;T
Polyphen		0.0	B;B;.;.
Vest4		0.21, 0.20
MutPred		0.56		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		0.67
MPC		1.0
ClinPred		0.052	T
GERP RS		2.5
Varity_R		0.043
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: rs2074528024; hg19: chr3-121973056;