NM_000388.4:c.2985G>C

Variant names:

• chr3-122284939-G-C
• rs201341173
• NM_000388.4:c.2985G>C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM1 PP2 BP4_Moderate

The NM_000388.4(CASR):​c.2985G>C​(p.Gln995His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,864 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: 33)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: CASR NM_000388.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.268

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.

• PM1: In a topological_domain Cytoplasmic (size 215) in uniprot entity CASR_HUMAN there are 14 pathogenic changes around while only 2 benign (88%) in NM_000388.4
• 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=0.13259292).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASR	NM_000388.4	c.2985G>C	p.Gln995His	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.2985G>C	p.Gln995His	missense_variant	Exon 7 of 7	1	NM_000388.4	ENSP00000491584.2
CASR	ENST00000498619.4	c.3015G>C	p.Gln1005His	missense_variant	Exon 7 of 7	1		ENSP00000420194.1
CASR	ENST00000638421.1	c.2985G>C	p.Gln995His	missense_variant	Exon 7 of 7	5		ENSP00000492190.1
CASR	ENST00000490131.7	c.2754G>C	p.Gln918His	missense_variant	Exon 5 of 5	5		ENSP00000418685.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461864 Hom.: 0 Cov.: 71 AF XY: 0.00000275 AC XY: 2 AN XY: 727236

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: 0.00000719

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Nephrolithiasis/nephrocalcinosis Uncertain:1

Apr 01, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Q995H variant (also known as c.2985G>C), located in coding exon 6 of the CASR gene, results from a G to C substitution at nucleotide position 2985. The glutamine at codon 995 is replaced by histidine, an amino acid with highly 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

Aug 26, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 995 of the CASR protein (p.Gln995His). 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: 463942). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The histidine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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	0.097
BayesDel_addAF	Benign	-0.020	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	11
DANN	Benign	0.97
DEOGEN2	Benign	0.30	T;T;.;.
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.31
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.87	.;D;D;D
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.13	T;T;T;T
MetaSVM	Benign	-0.37	T
MutationAssessor	Benign	1.1	L;L;.;.
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.53	.;.;N;.
REVEL	Benign	0.26
Sift	Uncertain	0.0080	.;.;D;.
Sift4G	Uncertain	0.023	.;.;D;.
Polyphen		0.0	B;B;.;.
Vest4		0.045
MutPred		0.094		.;.;Gain of glycosylation at S1002 (P = 0.0323);.;
MVP		0.84
MPC		0.57
ClinPred		0.24	T
GERP RS		1.7
Varity_R		0.089
gMVP		0.29

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: rs201341173; hg19: chr3-122003786;