3-122284910-G-T

Position:

• chr3-122284910-G-T

Variant summary

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

The NM_000388.4(CASR):​c.2956G>T​(p.Ala986Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.132 in 1,614,034 control chromosomes in the GnomAD database, including 15,629 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1222 hom., cov: 33)
  • Exomes 𝑓: 0.13 (14407 hom.)
• Consequence: CASR NM_000388.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:16 O:1
• Conservation: PhyloP100: 3.23

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 topological_domain Cytoplasmic (size 215) in uniprot entity CASR_HUMAN there are 14 pathogenic changes around while only 2 benign (88%) in NM_000388.4
• 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=0.0016186535).
• BP6: Variant 3-122284910-G-T is Benign according to our data. Variant chr3-122284910-G-T is described in ClinVar as [Benign]. Clinvar id is 8349.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-122284910-G-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.173 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CASR	NM_000388.4	c.2956G>T	p.Ala986Ser	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.2956G>T	p.Ala986Ser	missense_variant	7/7	1	NM_000388.4	ENSP00000491584.2
CASR	ENST00000498619.4	c.2986G>T	p.Ala996Ser	missense_variant	7/7	1		ENSP00000420194.1
CASR	ENST00000638421.1	c.2956G>T	p.Ala986Ser	missense_variant	7/7	5		ENSP00000492190.1
CASR	ENST00000490131.7	c.2725G>T	p.Ala909Ser	missense_variant	5/5	5		ENSP00000418685.2

Frequencies

GnomAD3 genomes AF: 0.110 AC: 16746 AN: 152080 Hom.: 1221 Cov.: 33

Gnomad AFR AF: 0.0350

Gnomad AMI AF: 0.0965

Gnomad AMR AF: 0.121

Gnomad ASJ AF: 0.263

Gnomad EAS AF: 0.0319

Gnomad SAS AF: 0.183

Gnomad FIN AF: 0.137

Gnomad MID AF: 0.259

Gnomad NFE AF: 0.141

Gnomad OTH AF: 0.142

GnomAD3 exomes AF: 0.129 AC: 32291 AN: 251286 Hom.: 2516 AF XY: 0.137 AC XY: 18616 AN XY: 135808

Gnomad AFR exome AF: 0.0332

Gnomad AMR exome AF: 0.0820

Gnomad ASJ exome AF: 0.259

Gnomad EAS exome AF: 0.0301

Gnomad SAS exome AF: 0.194

Gnomad FIN exome AF: 0.135

Gnomad NFE exome AF: 0.140

Gnomad OTH exome AF: 0.161

GnomAD4 exome AF: 0.134 AC: 195949 AN: 1461836 Hom.: 14407 Cov.: 73 AF XY: 0.138 AC XY: 100135 AN XY: 727212

Gnomad4 AFR exome AF: 0.0340

Gnomad4 AMR exome AF: 0.0868

Gnomad4 ASJ exome AF: 0.260

Gnomad4 EAS exome AF: 0.0224

Gnomad4 SAS exome AF: 0.194

Gnomad4 FIN exome AF: 0.135

Gnomad4 NFE exome AF: 0.134

Gnomad4 OTH exome AF: 0.143

GnomAD4 genome AF: 0.110 AC: 16743 AN: 152198 Hom.: 1222 Cov.: 33 AF XY: 0.111 AC XY: 8274 AN XY: 74416

Gnomad4 AFR AF: 0.0350

Gnomad4 AMR AF: 0.121

Gnomad4 ASJ AF: 0.263

Gnomad4 EAS AF: 0.0316

Gnomad4 SAS AF: 0.183

Gnomad4 FIN AF: 0.137

Gnomad4 NFE AF: 0.141

Gnomad4 OTH AF: 0.141

Alfa AF: 0.142 Hom.: 4476

Bravo AF: 0.104

TwinsUK AF: 0.131 AC: 487

ALSPAC AF: 0.130 AC: 501

ESP6500AA AF: 0.0406 AC: 179

ESP6500EA AF: 0.148 AC: 1272

ExAC AF: 0.127 AC: 15416

Asia WGS AF: 0.112 AC: 389 AN: 3478

EpiCase AF: 0.147

EpiControl AF: 0.159

ClinVar

Significance: Benign

Submissions summary: Benign:16 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:8

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 21, 2017	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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 05, 2017	p.Ala996Ser in exon 7 of CASR: This variant is not expected to have clinical sig nificance because it has been identified in 19.5% (3223/16508) of South Asian ch romosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute. org; dbSNP rs1801725). -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 07, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 17, 2017	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

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

Aug 30, 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. -

Familial hypocalciuric hypercalcemia 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). 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. -

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). 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. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Malignant tumor of breast Benign:1

Benign, no assertion criteria provided

clinical testing

Center of Medical Genetics and Primary Health Care

-

- -

Serum calcium level Other:1

association, no assertion criteria provided

literature only

OMIM

Jul 25, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	13
DANN	Uncertain	0.98
DEOGEN2	Benign	0.28	T;T;.;.
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.098
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.82	.;T;T;T
MetaRNN	Benign	0.0016	T;T;T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	1.8	L;L;.;.
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.32	.;.;N;.
REVEL	Benign	0.29
Sift	Benign	0.19	.;.;T;.
Sift4G	Benign	0.20	.;.;T;.
Polyphen		0.20	B;B;.;.
Vest4		0.029
MPC		0.56
ClinPred		0.0092	T
GERP RS		4.9
Varity_R		0.094
gMVP		0.21

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1801725; hg19: chr3-122003757; COSMIC: COSV56138925;