NM_000388.4:c.3031G>C

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_000388.4(CASR):c.3031G>C(p.Glu1011Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.953 in 1,614,136 control chromosomes in the GnomAD database, including 733,487 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. E1011E) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.92 ( 64966 hom., cov: 32)

Exomes 𝑓: 0.96 ( 668521 hom. )

Consequence

CASR
NM_000388.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 1.20

Publications

107 publications found

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 Gene-Disease associations (from GenCC):

autosomal dominant hypocalcemia 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Illumina, ClinGen, Labcorp Genetics (formerly Invitae)
familial hypocalciuric hypercalcemia 1
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Illumina, Orphanet, Genomics England PanelApp
neonatal severe primary hyperparathyroidism
Inheritance: AR, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, Labcorp Genetics (formerly Invitae)
autosomal dominant hypocalcemia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
epilepsy, idiopathic generalized, susceptibility to, 8
Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
epilepsy
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

CASR links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

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 neonatal severe primary hyperparathyroidism, autosomal dominant hypocalcemia 1, familial hypocalciuric hypercalcemia 1, epilepsy, autosomal dominant hypocalcemia, epilepsy, idiopathic generalized, susceptibility to, 8.

BP4

Computational evidence support a benign effect (MetaRNN=7.8220154E-7).

BP6

Variant 3-122284985-G-C is Benign according to our data. Variant chr3-122284985-G-C is described in ClinVar as Benign. ClinVar VariationId is 166799.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.959 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASR	NM_000388.4 link	c.3031G>C	p.Glu1011Gln	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.3031G>C	p.Glu1011Gln	missense_variant	Exon 7 of 7	1	NM_000388.4	ENSP00000491584.2	P41180-1
CASR	ENST00000498619.4 link	c.3061G>C	p.Glu1021Gln	missense_variant	Exon 7 of 7	1		ENSP00000420194.1	P41180-2
CASR	ENST00000638421.1 link	c.3031G>C	p.Glu1011Gln	missense_variant	Exon 7 of 7	5		ENSP00000492190.1	P41180-1
CASR	ENST00000490131.7 link	c.2800G>C	p.Glu934Gln	missense_variant	Exon 5 of 5	5		ENSP00000418685.2	A0A1X7SBX3

Frequencies

GnomAD3 genomes

AF:

0.922

AC:

140224

AN:

152142

Hom.:

64924

Cov.:

show subpopulations

Gnomad AFR

AF:

0.826

Gnomad AMI

AF:

0.946

Gnomad AMR

AF:

0.969

Gnomad ASJ

AF:

0.984

Gnomad EAS

AF:

0.981

Gnomad SAS

AF:

0.956

Gnomad FIN

AF:

0.917

Gnomad MID

AF:

0.972

Gnomad NFE

AF:

0.959

Gnomad OTH

AF:

0.939

GnomAD2 exomes

AF:

0.950

AC:

238820

AN:

251384

AF XY:

0.952

show subpopulations

Gnomad AFR exome

AF:

0.824

Gnomad AMR exome

AF:

0.982

Gnomad ASJ exome

AF:

0.985

Gnomad EAS exome

AF:

0.984

Gnomad FIN exome

AF:

0.918

Gnomad NFE exome

AF:

0.955

Gnomad OTH exome

AF:

0.963

GnomAD4 exome

AF:

0.956

AC:

1397542

AN:

1461876

Hom.:

668521

Cov.:

AF XY:

0.956

AC XY:

695263

AN XY:

727242

show subpopulations

African (AFR)

AF:

0.820

AC:

27446

AN:

33478

American (AMR)

AF:

0.981

AC:

43858

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.984

AC:

25716

AN:

26136

East Asian (EAS)

AF:

0.985

AC:

39092

AN:

39698

South Asian (SAS)

AF:

0.952

AC:

82113

AN:

86256

European-Finnish (FIN)

AF:

0.919

AC:

49074

AN:

53420

Middle Eastern (MID)

AF:

0.972

AC:

5607

AN:

5768

European-Non Finnish (NFE)

AF:

0.959

AC:

1066853

AN:

1112002

Other (OTH)

AF:

0.957

AC:

57783

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

4167

8333

12500

16666

20833

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21632

43264

64896

86528

108160

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.922

AC:

140324

AN:

152260

Hom.:

64966

Cov.:

AF XY:

0.923

AC XY:

68682

AN XY:

74436

show subpopulations

African (AFR)

AF:

0.826

AC:

34290

AN:

41522

American (AMR)

AF:

0.969

AC:

14831

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.984

AC:

3415

AN:

3472

East Asian (EAS)

AF:

0.981

AC:

5090

AN:

5188

South Asian (SAS)

AF:

0.956

AC:

4616

AN:

4826

European-Finnish (FIN)

AF:

0.917

AC:

9716

AN:

10592

Middle Eastern (MID)

AF:

0.969

AC:

285

AN:

294

European-Non Finnish (NFE)

AF:

0.959

AC:

65229

AN:

68036

Other (OTH)

AF:

0.940

AC:

1989

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

542

1085

1627

2170

2712

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

906

1812

2718

3624

4530

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.957

Hom.:

52739

Bravo

AF:

0.923

TwinsUK

AF:

0.962

AC:

3568

ALSPAC

AF:

0.959

AC:

3696

ESP6500AA

AF:

0.836

AC:

3685

ESP6500EA

AF:

0.960

AC:

8252

ExAC

AF:

0.945

AC:

114677

Asia WGS

AF:

0.955

AC:

3320

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Aug 22, 2013

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 21, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Glu1021Gln in exon 7 of CASR: This variant is not expected to have clinical si gnificance because it has been identified in 98.35% (8507/8650) of East Asian ch romosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute. org; dbSNP rs1801726). -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Autosomal dominant hypocalcemia 1

Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Familial hypocalciuric hypercalcemia 1

Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Neonatal severe primary hyperparathyroidism

Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.059

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Benign

0.55

Eigen

Benign

-0.58

Eigen_PC

Benign

-0.42

FATHMM_MKL

Benign

0.012

LIST_S2

Benign

0.054

.;T;T;T

MetaRNN

Benign

7.8e-7

T;T;T;T

MetaSVM

Benign

-0.94

PhyloP100

1.2

PrimateAI

Benign

0.31

PROVEAN

Benign

0.26

.;.;N;.

REVEL

Benign

0.24

Sift

Benign

1.0

.;.;T;.

Sift4G

Benign

0.85

.;.;T;.

Vest4

0.026

MPC

0.59

ClinPred

0.0033

GERP RS

5.8

Varity_R

0.057

gMVP

0.18

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over