rs150979829

Positions:

chr3-122284824-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM1PP2BP4_Moderate

The NM_000388.4(CASR):c.2870A>G(p.Gln957Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000193 in 1,604,600 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q957H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

CASR
NM_000388.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 0.605

Variant links:

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]

CASR links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM1

In a compositionally_biased_region Polar residues (size 69) in uniprot entity CASR_HUMAN there are 5 pathogenic changes around while only 2 benign (71%) in NM_000388.4

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=0.10220623).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CASR	NM_000388.4 linkuse as main transcript	c.2870A>G	p.Gln957Arg	missense_variant	7/7	ENST00000639785.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CASR	ENST00000639785.2 linkuse as main transcript	c.2870A>G	p.Gln957Arg	missense_variant	7/7	1	NM_000388.4	P1	P41180-1
CASR	ENST00000498619.4 linkuse as main transcript	c.2900A>G	p.Gln967Arg	missense_variant	7/7	1			P41180-2
CASR	ENST00000638421.1 linkuse as main transcript	c.2870A>G	p.Gln957Arg	missense_variant	7/7	5		P1	P41180-1
CASR	ENST00000490131.7 linkuse as main transcript	c.2639A>G	p.Gln880Arg	missense_variant	5/5	5

Frequencies

GnomAD3 genomes

AF:

0.0000592

AC:

AN:

152074

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

251376

Hom.:

AF XY:

0.0000294

AC XY:

AN XY:

135880

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000440

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000151

AC:

AN:

1452526

Hom.:

Cov.:

AF XY:

0.0000221

AC XY:

AN XY:

722978

show subpopulations

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:

0.0000190

Gnomad4 OTH exome

AF:

0.0000167

GnomAD4 genome

AF:

0.0000592

AC:

AN:

152074

Hom.:

Cov.:

AF XY:

0.0000808

AC XY:

AN XY:

74288

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000986

Hom.:

Bravo

AF:

0.0000227

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Nephrolithiasis/nephrocalcinosis

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 12, 2022

The p.Q957R variant (also known as c.2870A>G), located in coding exon 6 of the CASR gene, results from an A to G substitution at nucleotide position 2870. The glutamine at codon 957 is replaced by arginine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. 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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 07, 2023

This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 957 of the CASR protein (p.Gln957Arg). This variant is present in population databases (rs150979829, gnomAD 0.005%). 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: 237765). 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 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. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Jun 20, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.045

BayesDel_noAF

Benign

-0.24

CADD

Benign

3.0

DANN

Benign

0.53

DEOGEN2

Benign

0.28

T;T;.;.

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.95

FATHMM_MKL

Benign

0.43

LIST_S2

Benign

0.42

.;T;T;T

M_CAP

Benign

0.035

MetaRNN

Benign

0.10

T;T;T;T

MetaSVM

Benign

-0.74

MutationAssessor

Benign

1.0

L;L;.;.

MutationTaster

Benign

0.99

N;N;N

PrimateAI

Benign

0.40

PROVEAN

Benign

-0.26

.;.;N;.

REVEL

Benign

0.20

Sift

Benign

0.28

.;.;T;.

Sift4G

Benign

0.60

.;.;T;.

Polyphen

0.010

B;B;.;.

Vest4

0.20

MVP

0.71

MPC

0.66

ClinPred

0.050

GERP RS

1.3

Varity_R

0.053

gMVP

0.33

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over