rs9869985

Positions:

• chr3-122257406-G-A
• chr3-122257406-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000388.4(CASR):​c.492+19G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.952 in 1,604,058 control chromosomes in the GnomAD database, including 728,269 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.92 (64413 hom., cov: 31)
  • Exomes 𝑓: 0.96 (663856 hom.)
• Consequence: CASR NM_000388.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -0.994

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 3-122257406-G-A is Benign according to our data. Variant chr3-122257406-G-A is described in ClinVar as [Benign]. Clinvar id is 35799.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-122257406-G-A is described in Lovd as [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.492+19G>A		intron_variant		ENST00000639785.2	NP_000379.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CASR	ENST00000639785.2	c.492+19G>A		intron_variant		1	NM_000388.4	ENSP00000491584.2

Frequencies

GnomAD3 genomes AF: 0.918 AC: 139564 AN: 152094 Hom.: 64374 Cov.: 31

Gnomad AFR AF: 0.811

Gnomad AMI AF: 0.946

Gnomad AMR AF: 0.967

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: 0.938

GnomAD3 exomes AF: 0.949 AC: 235703 AN: 248316 Hom.: 112074 AF XY: 0.951 AC XY: 128020 AN XY: 134620

Gnomad AFR exome AF: 0.809

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: 0.917

Gnomad NFE exome AF: 0.955

Gnomad OTH exome AF: 0.964

GnomAD4 exome AF: 0.956 AC: 1387778 AN: 1451846 Hom.: 663856 Cov.: 28 AF XY: 0.956 AC XY: 690837 AN XY: 722642

Gnomad4 AFR exome AF: 0.807

Gnomad4 AMR exome AF: 0.980

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: 0.960

Gnomad4 OTH exome AF: 0.956

GnomAD4 genome AF: 0.918 AC: 139661 AN: 152212 Hom.: 64413 Cov.: 31 AF XY: 0.919 AC XY: 68371 AN XY: 74426

Gnomad4 AFR AF: 0.811

Gnomad4 AMR AF: 0.968

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: 0.939

Alfa AF: 0.956 Hom.: 71505

Bravo AF: 0.918

Asia WGS AF: 0.955 AC: 3320 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 22, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 13, 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, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 13, 2017	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

- -

Familial hypocalciuric hypercalcemia Benign:1

Benign, criteria provided, single submitter

clinical testing;curation

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 18, 2011

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.089
DANN	Benign	0.47

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs9869985; hg19: chr3-121976253;