rs139417576

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 3P and 6B. PM1PP2BP4BP6BS1

The NM_000388.4(CASR):c.2237C>T(p.Ala746Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000279 in 1,613,934 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A746T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00019 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

CASR
NM_000388.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:1

Conservation

PhyloP100: 6.15

Publications

2 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: Likely_benign. The variant received -3 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 22 uncertain 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 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=0.42059687).

BP6

Variant 3-122284191-C-T is Benign according to our data. Variant chr3-122284191-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 463921.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00019 (29/152292) while in subpopulation AFR AF = 0.000698 (29/41566). AF 95% confidence interval is 0.000498. There are 0 homozygotes in GnomAd4. There are 14 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASR	NM_000388.4 link	c.2237C>T	p.Ala746Val	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.2237C>T	p.Ala746Val	missense_variant	Exon 7 of 7	1	NM_000388.4	ENSP00000491584.2	P41180-1
CASR	ENST00000498619.4 link	c.2267C>T	p.Ala756Val	missense_variant	Exon 7 of 7	1		ENSP00000420194.1	P41180-2
CASR	ENST00000638421.1 link	c.2237C>T	p.Ala746Val	missense_variant	Exon 7 of 7	5		ENSP00000492190.1	P41180-1
CASR	ENST00000490131.7 link	c.2006C>T	p.Ala669Val	missense_variant	Exon 5 of 5	5		ENSP00000418685.2	A0A1X7SBX3

Frequencies

GnomAD3 genomes

AF:

0.000191

AC:

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000700

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000280

AC:

AN:

250410

AF XY:

0.0000221

show subpopulations

Gnomad AFR exome

AF:

0.000434

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000109

AC:

AN:

1461642

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727140

show subpopulations

African (AFR)

AF:

0.000329

AC:

AN:

33476

American (AMR)

AF:

0.00

AC:

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53252

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111958

Other (OTH)

AF:

0.0000497

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.000190

AC:

AN:

152292

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.000698

AC:

AN:

41566

American (AMR)

AF:

0.00

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.0000322

Hom.:

Bravo

AF:

0.000227

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000494

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 22, 2023

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: CASR c.2237C>T (p.Ala746Val) results in a non-conservative amino acid change located in the GPCR family 3, C-terminal domain (IPR017978) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.3e-05 in 281788 control chromosomes. The observed variant frequency is approximately 3.41 fold of the estimated maximal expected allele frequency for a pathogenic variant in CASR causing Familial Hypocalciuric Hypercalcemia phenotype (1.3e-05), suggesting that the variant is benign. c.2237C>T has been reported in the literature in at-least two individuals affected with Familial Hypocalciuric Hypercalcemia (example, Vargas-Poussou_2016, Hureaux_2019). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 31189130, 31672324, 26963950, 34088669). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. One submitter classified the variant as likely benign, and one submitter classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

CASR-related disorder

Uncertain:1

Jun 27, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The CASR c.2267C>T variant is predicted to result in the amino acid substitution p.Ala756Val. This variant, described as c.2237C>T (p.Ala746Val) in an alternate transcript (NM_000388.3), has been reported in at least one individual with familial hypocalciuric hypercalcemia (Table 1, Vargas-Poussou R et al. 2016. PubMed ID: 26963950; Supplementary Table S1, Hureaux M et al. 2019. PubMed ID: 31672324). This variant is reported in 0.048% of alleles in individuals of African descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Autosomal dominant hypocalcemia 1;C1809471:Familial hypocalciuric hypercalcemia

Uncertain:1

Nov 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 746 of the CASR protein (p.Ala746Val). This variant is present in population databases (rs139417576, gnomAD 0.05%). This missense change has been observed in individual(s) with familial hypocalciuric hypercalcemia (PMID: 26963950, 31672324). ClinVar contains an entry for this variant (Variation ID: 463921). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬¨‚Ä†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

May 15, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The CASR c.2237C>T; p.Ala746Val variant (rs139417576; ClinVar ID: 463921) is reported in the literature in several individuals affected with hypercalcemia hypocalciuria (Hureaux 2019, Vargas-Poussou 2016). This variant is found in the African population with an allele frequency of 0.05% (12/24,832 alleles) in the Genome Aggregation Database (v2.1.1). Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.652). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Hureaux M et al. High-throughput sequencing contributes to the diagnosis of tubulopathies and familial hypercalcemia hypocalciuria in adults. Kidney Int. 2019 Dec;96(6):1408-1416. PMID: 31672324. Vargas-Poussou R et al. Familial Hypocalciuric Hypercalcemia Types 1 and 3 and Primary Hyperparathyroidism: Similarities and Differences. J Clin Endocrinol Metab. 2016 May;101(5):2185-95. PMID: 26963950. -

Nephrolithiasis/nephrocalcinosis

Benign:1

Feb 23, 2023

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.012

BayesDel_noAF

Uncertain

0.10

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.71

D;D;.;.

Eigen

Pathogenic

0.70

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.95

.;D;D;D

M_CAP

Uncertain

0.23

MetaRNN

Benign

0.42

T;T;T;T

MetaSVM

Uncertain

0.58

MutationAssessor

Benign

1.3

L;L;.;.

PhyloP100

6.2

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-2.1

.;.;N;.

REVEL

Pathogenic

0.65

Sift

Uncertain

0.028

.;.;D;.

Sift4G

Uncertain

0.035

.;.;D;.

Polyphen

1.0

D;D;.;.

Vest4

0.74

MVP

0.97

MPC

1.2

ClinPred

0.29

GERP RS

5.9

Varity_R

0.40

gMVP

0.80

Mutation Taster

=5/95

disease causing

(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