3-122284910-G-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 3P and 20B. PM1PP2BP4_StrongBP6_Very_StrongBA1

The NM_000388.4(CASR):c.2956G>T(p.Ala986Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.132 in 1,614,034 control chromosomes in the GnomAD database, including 15,629 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.11 ( 1222 hom., cov: 33)

Exomes 𝑓: 0.13 ( 14407 hom. )

Consequence

CASR
NM_000388.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:16O:1

Conservation

PhyloP100: 3.23

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 Benign. Variant got -17 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=0.0016186535).

BP6

Variant 3-122284910-G-T is Benign according to our data. Variant chr3-122284910-G-T is described in ClinVar as [Benign]. Clinvar id is 8349.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-122284910-G-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.173 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASR	NM_000388.4 link	c.2956G>T	p.Ala986Ser	missense_variant	Exon 7 of 7	ENST00000639785.2	NP_000379.3	P41180-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CASR	ENST00000639785.2 link	c.2956G>T	p.Ala986Ser	missense_variant	Exon 7 of 7	1	NM_000388.4	ENSP00000491584.2	P41180-1
CASR	ENST00000498619.4 link	c.2986G>T	p.Ala996Ser	missense_variant	Exon 7 of 7	1		ENSP00000420194.1	P41180-2
CASR	ENST00000638421.1 link	c.2956G>T	p.Ala986Ser	missense_variant	Exon 7 of 7	5		ENSP00000492190.1	P41180-1
CASR	ENST00000490131.7 link	c.2725G>T	p.Ala909Ser	missense_variant	Exon 5 of 5	5		ENSP00000418685.2	A0A1X7SBX3

Frequencies

GnomAD3 genomes

AF:

0.110

AC:

16746

AN:

152080

Hom.:

1221

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0350

Gnomad AMI

AF:

0.0965

Gnomad AMR

AF:

0.121

Gnomad ASJ

AF:

0.263

Gnomad EAS

AF:

0.0319

Gnomad SAS

AF:

0.183

Gnomad FIN

AF:

0.137

Gnomad MID

AF:

0.259

Gnomad NFE

AF:

0.141

Gnomad OTH

AF:

0.142

GnomAD3 exomes

AF:

0.129

AC:

32291

AN:

251286

Hom.:

2516

AF XY:

0.137

AC XY:

18616

AN XY:

135808

show subpopulations

Gnomad AFR exome

AF:

0.0332

Gnomad AMR exome

AF:

0.0820

Gnomad ASJ exome

AF:

0.259

Gnomad EAS exome

AF:

0.0301

Gnomad SAS exome

AF:

0.194

Gnomad FIN exome

AF:

0.135

Gnomad NFE exome

AF:

0.140

Gnomad OTH exome

AF:

0.161

GnomAD4 exome

AF:

0.134

AC:

195949

AN:

1461836

Hom.:

14407

Cov.:

AF XY:

0.138

AC XY:

100135

AN XY:

727212

show subpopulations

Gnomad4 AFR exome

AF:

0.0340

Gnomad4 AMR exome

AF:

0.0868

Gnomad4 ASJ exome

AF:

0.260

Gnomad4 EAS exome

AF:

0.0224

Gnomad4 SAS exome

AF:

0.194

Gnomad4 FIN exome

AF:

0.135

Gnomad4 NFE exome

AF:

0.134

Gnomad4 OTH exome

AF:

0.143

GnomAD4 genome

AF:

0.110

AC:

16743

AN:

152198

Hom.:

1222

Cov.:

AF XY:

0.111

AC XY:

8274

AN XY:

74416

show subpopulations

Gnomad4 AFR

AF:

0.0350

Gnomad4 AMR

AF:

0.121

Gnomad4 ASJ

AF:

0.263

Gnomad4 EAS

AF:

0.0316

Gnomad4 SAS

AF:

0.183

Gnomad4 FIN

AF:

0.137

Gnomad4 NFE

AF:

0.141

Gnomad4 OTH

AF:

0.141

Alfa

AF:

0.142

Hom.:

4476

Bravo

AF:

0.104

TwinsUK

AF:

0.131

AC:

487

ALSPAC

AF:

0.130

AC:

501

ESP6500AA

AF:

0.0406

AC:

179

ESP6500EA

AF:

0.148

AC:

1272

ExAC

AF:

0.127

AC:

15416

Asia WGS

AF:

0.112

AC:

389

AN:

3478

EpiCase

AF:

0.147

EpiControl

AF:

0.159

ClinVar

Significance: Benign

Submissions summary: Benign:16Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:8

Dec 21, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 17, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 05, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Ala996Ser in exon 7 of CASR: This variant is not expected to have clinical sig nificance because it has been identified in 19.5% (3223/16508) of South Asian ch romosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute. org; dbSNP rs1801725). -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 07, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Autosomal dominant hypocalcemia 1

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Nephrolithiasis/nephrocalcinosis

Benign:1

Aug 30, 2018

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Neonatal severe primary hyperparathyroidism

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Familial hypocalciuric hypercalcemia 1

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Autosomal dominant hypocalcemia 1;C1809471:Familial hypocalciuric hypercalcemia

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial hypoparathyroidism

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Malignant tumor of breast

Benign:1

Center of Medical Genetics and Primary Health Care

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Serum calcium level

Other:1

Jul 25, 2018

OMIM

Significance: association

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.26

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.28

T;T;.;.

Eigen

Benign

-0.27

Eigen_PC

Benign

-0.098

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.82

.;T;T;T

MetaRNN

Benign

0.0016

T;T;T;T

MetaSVM

Benign

-0.86

MutationAssessor

Benign

1.8

L;L;.;.

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.32

.;.;N;.

REVEL

Benign

0.29

Sift

Benign

0.19

.;.;T;.

Sift4G

Benign

0.20

.;.;T;.

Polyphen

0.20

B;B;.;.

Vest4

0.029

MPC

0.56

ClinPred

0.0092

GERP RS

4.9

Varity_R

0.094

gMVP

0.21

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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