3-122284843-G-C

Variant names:

• chr3-122284843-G-C
• rs1060502859
• NM_000388.4:c.2889G>C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM1 PM2 PP2 BP4

The NM_000388.4(CASR):​c.2889G>C​(p.Lys963Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CASR NM_000388.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.08

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 4 ACMG points.

• PM1: In a compositionally_biased_region Polar residues (size 69) in uniprot entity CASR_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000388.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the CASR gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 114 curated pathogenic missense variants (we use a threshold of 10). The gene has 10 curated benign missense variants. Gene score misZ: 3.1237 (above the threshold of 3.09). Trascript score misZ: 4.8257 (above the threshold of 3.09). GenCC associations: The gene is linked to 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=0.30104935).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASR	NM_000388.4	c.2889G>C	p.Lys963Asn	missense_variant	Exon 7 of 7	ENST00000639785.2	NP_000379.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CASR	ENST00000639785.2	c.2889G>C	p.Lys963Asn	missense_variant	Exon 7 of 7	1	NM_000388.4	ENSP00000491584.2
CASR	ENST00000498619.4	c.2919G>C	p.Lys973Asn	missense_variant	Exon 7 of 7	1		ENSP00000420194.1
CASR	ENST00000638421.1	c.2889G>C	p.Lys963Asn	missense_variant	Exon 7 of 7	5		ENSP00000492190.1
CASR	ENST00000490131.7	c.2658G>C	p.Lys886Asn	missense_variant	Exon 5 of 5	5		ENSP00000418685.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 71

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Nephrolithiasis/nephrocalcinosis Uncertain:1

Jul 09, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.K963N variant (also known as c.2889G>C), located in coding exon 6 of the CASR gene, results from a G to C substitution at nucleotide position 2889. The lysine at codon 963 is replaced by asparagine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated 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

Dec 03, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 410354). This variant has not been reported in the literature in individuals affected with CASR-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.007%). This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 963 of the CASR protein (p.Lys963Asn). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
BayesDel_addAF	Uncertain	0.040	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	T;T;.;.
Eigen	Benign	-0.10
Eigen_PC	Benign	0.065
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.82	.;T;T;T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.30	T;T;T;T
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Benign	1.7	L;L;.;.
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-0.21	.;.;N;.
REVEL	Benign	0.29
Sift	Uncertain	0.0050	.;.;D;.
Sift4G	Uncertain	0.016	.;.;D;.
Polyphen		0.12	B;B;.;.
Vest4		0.40
MutPred		0.39		.;.;Loss of methylation at K973 (P = 2e-04);.;
MVP		0.86
MPC		0.99
ClinPred		0.82	D
GERP RS		4.7
Varity_R		0.26
gMVP		0.39

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: rs1060502859; hg19: chr3-122003690;