rs1042636

Positions:

• chr3-122284922-A-G

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 3P and 20B. PM1 PP2 BP4_Strong BP6_Very_Strong BA1

The ENST00000639785.2(CASR):​c.2968A>G​(p.Arg990Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.102 in 1,614,046 control chromosomes in the GnomAD database, including 15,462 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R990K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.098 (1495 hom., cov: 33)
  • Exomes 𝑓: 0.10 (13967 hom.)
• Consequence: CASR ENST00000639785.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 2.67

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]

ACMG classification

Verdict is Benign. Variant got -17 ACMG points.

• PM1: In a region_of_interest Disordered (size 20) in uniprot entity CASR_HUMAN there are 6 pathogenic changes around while only 2 benign (75%) in ENST00000639785.2
• 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=3.8957596E-4).
• BP6: Variant 3-122284922-A-G is Benign according to our data. Variant chr3-122284922-A-G is described in ClinVar as [Benign]. Clinvar id is 198071.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-122284922-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.504 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CASR	NM_000388.4	c.2968A>G	p.Arg990Gly	missense_variant	7/7	ENST00000639785.2	NP_000379.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CASR	ENST00000639785.2	c.2968A>G	p.Arg990Gly	missense_variant	7/7	1	NM_000388.4	ENSP00000491584	P1
CASR	ENST00000498619.4	c.2998A>G	p.Arg1000Gly	missense_variant	7/7	1		ENSP00000420194
CASR	ENST00000638421.1	c.2968A>G	p.Arg990Gly	missense_variant	7/7	5		ENSP00000492190	P1
CASR	ENST00000490131.7	c.2737A>G	p.Arg913Gly	missense_variant	5/5	5		ENSP00000418685

Frequencies

GnomAD3 genomes AF: 0.0975 AC: 14837 AN: 152102 Hom.: 1486 Cov.: 33

Gnomad AFR AF: 0.0412

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.177

Gnomad ASJ AF: 0.0450

Gnomad EAS AF: 0.519

Gnomad SAS AF: 0.230

Gnomad FIN AF: 0.100

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0766

Gnomad OTH AF: 0.0884

GnomAD3 exomes AF: 0.151 AC: 37928 AN: 251272 Hom.: 5268 AF XY: 0.146 AC XY: 19886 AN XY: 135826

Gnomad AFR exome AF: 0.0419

Gnomad AMR exome AF: 0.270

Gnomad ASJ exome AF: 0.0401

Gnomad EAS exome AF: 0.530

Gnomad SAS exome AF: 0.207

Gnomad FIN exome AF: 0.106

Gnomad NFE exome AF: 0.0743

Gnomad OTH exome AF: 0.115

GnomAD4 exome AF: 0.103 AC: 150360 AN: 1461826 Hom.: 13967 Cov.: 73 AF XY: 0.105 AC XY: 76083 AN XY: 727222

Gnomad4 AFR exome AF: 0.0388

Gnomad4 AMR exome AF: 0.257

Gnomad4 ASJ exome AF: 0.0406

Gnomad4 EAS exome AF: 0.541

Gnomad4 SAS exome AF: 0.202

Gnomad4 FIN exome AF: 0.106

Gnomad4 NFE exome AF: 0.0761

Gnomad4 OTH exome AF: 0.118

GnomAD4 genome AF: 0.0977 AC: 14870 AN: 152220 Hom.: 1495 Cov.: 33 AF XY: 0.103 AC XY: 7699 AN XY: 74432

Gnomad4 AFR AF: 0.0412

Gnomad4 AMR AF: 0.177

Gnomad4 ASJ AF: 0.0450

Gnomad4 EAS AF: 0.520

Gnomad4 SAS AF: 0.231

Gnomad4 FIN AF: 0.100

Gnomad4 NFE AF: 0.0766

Gnomad4 OTH AF: 0.0932

Alfa AF: 0.0870 Hom.: 2664

Bravo AF: 0.100

TwinsUK AF: 0.0734 AC: 272

ALSPAC AF: 0.0802 AC: 309

ESP6500AA AF: 0.0429 AC: 189

ESP6500EA AF: 0.0731 AC: 629

ExAC AF: 0.145 AC: 17658

Asia WGS AF: 0.367 AC: 1274 AN: 3478

EpiCase AF: 0.0721

EpiControl AF: 0.0666

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 14, 2015	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. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 21, 2015	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 10, 2012	- -

Familial hypocalciuric hypercalcemia 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Autosomal dominant hypocalcemia 1 Benign:1

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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Nephrolithiasis/nephrocalcinosis Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 12, 2018

This alteration is classified as 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

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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Autosomal dominant hypocalcemia 1;C1809471:Familial hypocalciuric hypercalcemia Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Familial hypoparathyroidism Benign:1

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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.13
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.36	T;T;.;.
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.068
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.87	.;D;D;D
MetaRNN	Benign	0.00039	T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.7	L;L;.;.
MutationTaster	Benign	0.015	P;P;P
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.79	.;.;N;.
REVEL	Uncertain	0.44
Sift	Uncertain	0.021	.;.;D;.
Sift4G	Uncertain	0.0060	.;.;D;.
Polyphen		0.15	B;B;.;.
Vest4		0.051
MPC		0.77
ClinPred		0.027	T
GERP RS		3.3
Varity_R		0.29
gMVP		0.44

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

Other links and lift over

dbSNP: rs1042636; hg19: chr3-122003769; COSMIC: COSV56139527;