rs200039241

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4BP6BS1

The NM_000388.4(CASR):c.854G>A(p.Arg285Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000297 in 1,614,080 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict 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. R285W) has been classified as Benign.

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

CASR
NM_000388.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

Conservation

PhyloP100: 3.02

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 Likely_benign. Variant got -5 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 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=0.27199456).

BP6

Variant 3-122261889-G-A is Benign according to our data. Variant chr3-122261889-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 237773.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2}.

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000092 (14/152190) while in subpopulation AMR AF= 0.00072 (11/15282). AF 95% confidence interval is 0.000403. There are 0 homozygotes in gnomad4. There are 11 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASR	NM_000388.4 link	c.854G>A	p.Arg285Gln	missense_variant	Exon 4 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.854G>A	p.Arg285Gln	missense_variant	Exon 4 of 7	1	NM_000388.4	ENSP00000491584.2	P41180-1
CASR	ENST00000498619.4 link	c.854G>A	p.Arg285Gln	missense_variant	Exon 4 of 7	1		ENSP00000420194.1	P41180-2
CASR	ENST00000638421.1 link	c.854G>A	p.Arg285Gln	missense_variant	Exon 4 of 7	5		ENSP00000492190.1	P41180-1
CASR	ENST00000490131.7 link	c.854G>A	p.Arg285Gln	missense_variant	Exon 3 of 5	5		ENSP00000418685.2	A0A1X7SBX3

Frequencies

GnomAD3 genomes

AF:

0.0000920

AC:

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000720

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000438

AC:

AN:

251298

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135846

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000260

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:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000233

AC:

AN:

1461890

Hom.:

Cov.:

AF XY:

0.0000248

AC XY:

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000201

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:

0.0000198

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000920

AC:

AN:

152190

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000720

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000831

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Autosomal dominant hypocalcemia 1;C0342637:Familial hypocalciuric hypercalcemia 1;C1832615:Neonatal severe primary hyperparathyroidism;C2752062:Epilepsy, idiopathic generalized, susceptibility to, 8

Uncertain:1

Dec 24, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Uncertain:1

Nov 30, 2015

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nephrolithiasis/nephrocalcinosis

Benign:1

Aug 10, 2022

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. -

Autosomal dominant hypocalcemia 1;C1809471:Familial hypocalciuric hypercalcemia

Benign:1

Apr 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.26

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.39

T;T;.;.

Eigen

Benign

0.047

Eigen_PC

Benign

0.15

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.89

.;D;D;D

M_CAP

Benign

0.067

MetaRNN

Benign

0.27

T;T;T;T

MetaSVM

Benign

-0.40

MutationAssessor

Benign

1.7

L;L;L;.

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-1.3

.;.;N;N

REVEL

Uncertain

0.31

Sift

Benign

0.17

.;.;T;T

Sift4G

Benign

0.43

.;.;T;T

Polyphen

0.67

P;P;.;.

Vest4

0.31, 0.27

MutPred

0.47

Loss of MoRF binding (P = 0.0436);Loss of MoRF binding (P = 0.0436);Loss of MoRF binding (P = 0.0436);Loss of MoRF binding (P = 0.0436);

MVP

0.94

MPC

0.70

ClinPred

0.35

GERP RS

4.4

Varity_R

0.39

gMVP

0.67

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