rs62269092

Positions:

chr3-122261783-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_000388.4(CASR):c.748G>A(p.Glu250Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00283 in 1,614,256 control chromosomes in the GnomAD database, including 12 homozygotes. 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.0016 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0030 ( 12 hom. )

Consequence

CASR
NM_000388.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:19

Conservation

PhyloP100: 2.46

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 -19 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CASR. . Gene score misZ 3.1237 (greater than the threshold 3.09). Trascript score misZ 4.8257 (greater than threshold 3.09). GenCC has associacion of gene with 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=0.011199564).

BP6

Variant 3-122261783-G-A is Benign according to our data. Variant chr3-122261783-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 196262.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-122261783-G-A is described in Lovd as [Likely_benign]. Variant chr3-122261783-G-A is described in Lovd as [Pathogenic].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00156 (238/152366) while in subpopulation NFE AF= 0.00309 (210/68034). AF 95% confidence interval is 0.00274. There are 0 homozygotes in gnomad4. There are 91 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 12 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CASR	NM_000388.4 linkuse as main transcript	c.748G>A	p.Glu250Lys	missense_variant	4/7	ENST00000639785.2	NP_000379.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CASR	ENST00000639785.2 linkuse as main transcript	c.748G>A	p.Glu250Lys	missense_variant	4/7	1	NM_000388.4	ENSP00000491584	P1	P41180-1
CASR	ENST00000498619.4 linkuse as main transcript	c.748G>A	p.Glu250Lys	missense_variant	4/7	1		ENSP00000420194		P41180-2
CASR	ENST00000638421.1 linkuse as main transcript	c.748G>A	p.Glu250Lys	missense_variant	4/7	5		ENSP00000492190	P1	P41180-1
CASR	ENST00000490131.7 linkuse as main transcript	c.748G>A	p.Glu250Lys	missense_variant	3/5	5		ENSP00000418685

Frequencies

GnomAD3 genomes

AF:

0.00156

AC:

238

AN:

152248

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000555

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000282

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00309

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00152

AC:

383

AN:

251346

Hom.:

AF XY:

0.00152

AC XY:

207

AN XY:

135830

show subpopulations

Gnomad AFR exome

AF:

0.000492

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.000647

Gnomad NFE exome

AF:

0.00304

Gnomad OTH exome

AF:

0.00179

GnomAD4 exome

AF:

0.00296

AC:

4325

AN:

1461890

Hom.:

Cov.:

AF XY:

0.00291

AC XY:

2116

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.000358

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.00101

Gnomad4 NFE exome

AF:

0.00360

Gnomad4 OTH exome

AF:

0.00401

GnomAD4 genome

AF:

0.00156

AC:

238

AN:

152366

Hom.:

Cov.:

AF XY:

0.00122

AC XY:

AN XY:

74518

show subpopulations

Gnomad4 AFR

AF:

0.000553

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000282

Gnomad4 NFE

AF:

0.00309

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00238

Hom.:

Bravo

AF:

0.00152

TwinsUK

AF:

0.00431

AC:

ALSPAC

AF:

0.00389

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00384

AC:

ExAC

AF:

0.00184

AC:

223

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:19

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 05, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 20, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 13, 2018	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. -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	May 09, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 02, 2023	Variant summary: CASR c.748G>A (p.Glu250Lys) results in a conservative amino acid change located in the Receptor, ligand binding region (IPR001828) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0015 in 251346 control chromosomes. The observed variant frequency is approximately 121.9 fold of the estimated maximal expected allele frequency for a pathogenic variant in CASR causing Familial Hypocalciuric Hypercalcemia phenotype (1.3e-05), strongly suggesting that the variant is benign. c.748G>A has been reported in the literature in individuals affected with Familial Hypocalciuric Hypercalcemia and autosomal dominant hypocalcaemia with Hypercalciuria without strong evidence for causality (examples: Simonds_2002, Hannan_2012, Nissen_2007, Frank-Raue_2011). These data do not allow any conclusion about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function (Hannan_2012). These results showed no damaging effect of this variant. The following publications have been ascertained in the context of this evaluation (PMID: 22422767, 22192860, 11807402, 21521328). Twelve submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -

not provided

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	CASR: BP4 -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 31, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Familial hypocalciuric hypercalcemia 1

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Autosomal dominant hypocalcemia 1

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Nephrolithiasis/nephrocalcinosis

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 09, 2018

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. -

Neonatal severe primary hyperparathyroidism

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

Autosomal dominant hypocalcemia 1;C1809471:Familial hypocalciuric hypercalcemia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 19, 2022

- -

Familial hypoparathyroidism

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

Hereditary cancer-predisposing syndrome

Benign:1

Likely benign, criteria provided, single submitter

curation

Sema4, Sema4

Nov 16, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Uncertain

-0.050

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.40

T;T;.;.

Eigen

Benign

-0.34

Eigen_PC

Benign

-0.15

FATHMM_MKL

Benign

0.73

LIST_S2

Benign

0.83

.;T;T;T

M_CAP

Benign

0.015

MetaRNN

Benign

0.011

T;T;T;T

MetaSVM

Benign

-0.82

MutationAssessor

Benign

0.74

N;N;N;.

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.37

PROVEAN

Benign

-1.4

.;.;N;N

REVEL

Uncertain

0.40

Sift

Benign

0.17

.;.;T;T

Sift4G

Benign

0.45

.;.;T;T

Polyphen

0.0

B;B;.;.

Vest4

0.70, 0.65

MVP

0.79

MPC

0.68

ClinPred

0.0083

GERP RS

2.4

Varity_R

0.29

gMVP

0.51

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