rs9869985

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000388.4(CASR):c.492+19G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.952 in 1,604,058 control chromosomes in the GnomAD database, including 728,269 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.92 ( 64413 hom., cov: 31)

Exomes 𝑓: 0.96 ( 663856 hom. )

Consequence

CASR
NM_000388.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: -0.994

Publications

11 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BP6

Variant 3-122257406-G-A is Benign according to our data. Variant chr3-122257406-G-A is described in ClinVar as Benign. ClinVar VariationId is 35799.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.492+19G>A		intron_variant	Intron 3 of 6	ENST00000639785.2	NP_000379.3	P41180-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CASR	ENST00000639785.2 link	c.492+19G>A		intron_variant	Intron 3 of 6	1	NM_000388.4	ENSP00000491584.2		P41180-1

Frequencies

GnomAD3 genomes

AF:

0.918

AC:

139564

AN:

152094

Hom.:

64374

Cov.:

show subpopulations

Gnomad AFR

AF:

0.811

Gnomad AMI

AF:

0.946

Gnomad AMR

AF:

0.967

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:

0.938

GnomAD2 exomes

AF:

0.949

AC:

235703

AN:

248316

AF XY:

0.951

show subpopulations

Gnomad AFR exome

AF:

0.809

Gnomad AMR exome

AF:

0.982

Gnomad ASJ exome

AF:

0.985

Gnomad EAS exome

AF:

0.984

Gnomad FIN exome

AF:

0.917

Gnomad NFE exome

AF:

0.955

Gnomad OTH exome

AF:

0.964

GnomAD4 exome

AF:

0.956

AC:

1387778

AN:

1451846

Hom.:

663856

Cov.:

AF XY:

0.956

AC XY:

690837

AN XY:

722642

show subpopulations

African (AFR)

AF:

0.807

AC:

26847

AN:

33266

American (AMR)

AF:

0.980

AC:

43819

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.984

AC:

25647

AN:

26066

East Asian (EAS)

AF:

0.985

AC:

39001

AN:

39608

South Asian (SAS)

AF:

0.952

AC:

81892

AN:

86046

European-Finnish (FIN)

AF:

0.919

AC:

48273

AN:

52548

Middle Eastern (MID)

AF:

0.974

AC:

4954

AN:

5088

European-Non Finnish (NFE)

AF:

0.960

AC:

1059967

AN:

1104532

Other (OTH)

AF:

0.956

AC:

57378

AN:

59992

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

2853

5705

8558

11410

14263

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21450

42900

64350

85800

107250

<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:

0.918

AC:

139661

AN:

152212

Hom.:

64413

Cov.:

AF XY:

0.919

AC XY:

68371

AN XY:

74426

show subpopulations

African (AFR)

AF:

0.811

AC:

33663

AN:

41494

American (AMR)

AF:

0.968

AC:

14804

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.984

AC:

3415

AN:

3472

East Asian (EAS)

AF:

0.981

AC:

5077

AN:

5174

South Asian (SAS)

AF:

0.956

AC:

4608

AN:

4820

European-Finnish (FIN)

AF:

0.917

AC:

9731

AN:

10610

Middle Eastern (MID)

AF:

0.969

AC:

285

AN:

294

European-Non Finnish (NFE)

AF:

0.959

AC:

65234

AN:

68026

Other (OTH)

AF:

0.939

AC:

1981

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

548

1096

1645

2193

2741

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

904

1808

2712

3616

4520

<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:

0.951

Hom.:

91515

Bravo

AF:

0.918

Asia WGS

AF:

0.955

AC:

3320

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

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

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

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Dec 13, 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. -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jul 13, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

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

- -

Familial hypocalciuric hypercalcemia

Benign:1

Aug 18, 2011

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing;curation

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

0.089

(source)

DANN

Benign

0.47

PhyloP100

-0.99

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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