3-122284985-G-C

Position:

• chr3-122284985-G-C

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.3031G>C​(p.Glu1011Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.953 in 1,614,136 control chromosomes in the GnomAD database, including 733,487 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.92 (64966 hom., cov: 32)
  • Exomes 𝑓: 0.96 (668521 hom.)
• Consequence: CASR NM_000388.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 1.20

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=7.8220154E-7).
• BP6: Variant 3-122284985-G-C is Benign according to our data. Variant chr3-122284985-G-C is described in ClinVar as [Benign]. Clinvar id is 166799.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-122284985-G-C is described in Lovd as [Benign]. Variant chr3-122284985-G-C is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.959 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CASR	NM_000388.4	c.3031G>C	p.Glu1011Gln	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.3031G>C	p.Glu1011Gln	missense_variant	7/7	1	NM_000388.4	ENSP00000491584.2
CASR	ENST00000498619.4	c.3061G>C	p.Glu1021Gln	missense_variant	7/7	1		ENSP00000420194.1
CASR	ENST00000638421.1	c.3031G>C	p.Glu1011Gln	missense_variant	7/7	5		ENSP00000492190.1
CASR	ENST00000490131.7	c.2800G>C	p.Glu934Gln	missense_variant	5/5	5		ENSP00000418685.2

Frequencies

GnomAD3 genomes AF: 0.922 AC: 140224 AN: 152142 Hom.: 64924 Cov.: 32

Gnomad AFR AF: 0.826

Gnomad AMI AF: 0.946

Gnomad AMR AF: 0.969

Gnomad ASJ AF: 0.984

Gnomad EAS AF: 0.981

Gnomad SAS AF: 0.956

Gnomad FIN AF: 0.917

Gnomad MID AF: 0.972

Gnomad NFE AF: 0.959

Gnomad OTH AF: 0.939

GnomAD3 exomes AF: 0.950 AC: 238820 AN: 251384 Hom.: 113632 AF XY: 0.952 AC XY: 129304 AN XY: 135884

Gnomad AFR exome AF: 0.824

Gnomad AMR exome AF: 0.982

Gnomad ASJ exome AF: 0.985

Gnomad EAS exome AF: 0.984

Gnomad SAS exome AF: 0.952

Gnomad FIN exome AF: 0.918

Gnomad NFE exome AF: 0.955

Gnomad OTH exome AF: 0.963

GnomAD4 exome AF: 0.956 AC: 1397542 AN: 1461876 Hom.: 668521 Cov.: 65 AF XY: 0.956 AC XY: 695263 AN XY: 727242

Gnomad4 AFR exome AF: 0.820

Gnomad4 AMR exome AF: 0.981

Gnomad4 ASJ exome AF: 0.984

Gnomad4 EAS exome AF: 0.985

Gnomad4 SAS exome AF: 0.952

Gnomad4 FIN exome AF: 0.919

Gnomad4 NFE exome AF: 0.959

Gnomad4 OTH exome AF: 0.957

GnomAD4 genome AF: 0.922 AC: 140324 AN: 152260 Hom.: 64966 Cov.: 32 AF XY: 0.923 AC XY: 68682 AN XY: 74436

Gnomad4 AFR AF: 0.826

Gnomad4 AMR AF: 0.969

Gnomad4 ASJ AF: 0.984

Gnomad4 EAS AF: 0.981

Gnomad4 SAS AF: 0.956

Gnomad4 FIN AF: 0.917

Gnomad4 NFE AF: 0.959

Gnomad4 OTH AF: 0.940

Alfa AF: 0.957 Hom.: 52739

Bravo AF: 0.923

TwinsUK AF: 0.962 AC: 3568

ALSPAC AF: 0.959 AC: 3696

ESP6500AA AF: 0.836 AC: 3685

ESP6500EA AF: 0.960 AC: 8252

ExAC AF: 0.945 AC: 114677

Asia WGS AF: 0.955 AC: 3320 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 21, 2016	p.Glu1021Gln in exon 7 of CASR: This variant is not expected to have clinical si gnificance because it has been identified in 98.35% (8507/8650) of East Asian ch romosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute. org; dbSNP rs1801726). -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 22, 2013	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Autosomal dominant hypocalcemia 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Familial hypocalciuric hypercalcemia 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Neonatal severe primary hyperparathyroidism Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	14
DANN	Benign	0.55
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.054	.;T;T;T
MetaRNN	Benign	7.8e-7	T;T;T;T
MetaSVM	Benign	-0.94	T
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.26	.;.;N;.
REVEL	Benign	0.24
Sift	Benign	1.0	.;.;T;.
Sift4G	Benign	0.85	.;.;T;.
Vest4		0.026
MPC		0.59
ClinPred		0.0033	T
GERP RS		5.8
Varity_R		0.057
gMVP		0.18

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: rs1801726; hg19: chr3-122003832;