rs2270916

Positions:

• chr3-122282252-T-C

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.1732+16T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.135 in 1,613,346 control chromosomes in the GnomAD database, including 17,374 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1359 hom., cov: 32)
  • Exomes 𝑓: 0.14 (16015 hom.)
• Consequence: CASR NM_000388.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.75

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 3-122282252-T-C is Benign according to our data. Variant chr3-122282252-T-C is described in ClinVar as [Benign]. Clinvar id is 257605.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-122282252-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.384 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CASR	NM_000388.4	c.1732+16T>C		intron_variant		ENST00000639785.2	NP_000379.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CASR	ENST00000639785.2	c.1732+16T>C		intron_variant		1	NM_000388.4	ENSP00000491584	P1
CASR	ENST00000498619.4	c.1762+16T>C		intron_variant		1		ENSP00000420194
CASR	ENST00000490131.7	c.1501+16T>C		intron_variant		5		ENSP00000418685
CASR	ENST00000638421.1	c.1732+16T>C		intron_variant		5		ENSP00000492190	P1

Frequencies

GnomAD3 genomes AF: 0.116 AC: 17650 AN: 152104 Hom.: 1362 Cov.: 32

Gnomad AFR AF: 0.0616

Gnomad AMI AF: 0.307

Gnomad AMR AF: 0.0947

Gnomad ASJ AF: 0.0825

Gnomad EAS AF: 0.399

Gnomad SAS AF: 0.0729

Gnomad FIN AF: 0.128

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.133

Gnomad OTH AF: 0.115

GnomAD3 exomes AF: 0.130 AC: 32638 AN: 251462 Hom.: 3085 AF XY: 0.126 AC XY: 17157 AN XY: 135904

Gnomad AFR exome AF: 0.0600

Gnomad AMR exome AF: 0.0823

Gnomad ASJ exome AF: 0.0805

Gnomad EAS exome AF: 0.401

Gnomad SAS exome AF: 0.0619

Gnomad FIN exome AF: 0.125

Gnomad NFE exome AF: 0.134

Gnomad OTH exome AF: 0.125

GnomAD4 exome AF: 0.137 AC: 200715 AN: 1461126 Hom.: 16015 Cov.: 32 AF XY: 0.134 AC XY: 97454 AN XY: 726880

Gnomad4 AFR exome AF: 0.0579

Gnomad4 AMR exome AF: 0.0823

Gnomad4 ASJ exome AF: 0.0810

Gnomad4 EAS exome AF: 0.395

Gnomad4 SAS exome AF: 0.0630

Gnomad4 FIN exome AF: 0.124

Gnomad4 NFE exome AF: 0.141

Gnomad4 OTH exome AF: 0.125

GnomAD4 genome AF: 0.116 AC: 17642 AN: 152220 Hom.: 1359 Cov.: 32 AF XY: 0.117 AC XY: 8712 AN XY: 74416

Gnomad4 AFR AF: 0.0614

Gnomad4 AMR AF: 0.0945

Gnomad4 ASJ AF: 0.0825

Gnomad4 EAS AF: 0.399

Gnomad4 SAS AF: 0.0729

Gnomad4 FIN AF: 0.128

Gnomad4 NFE AF: 0.133

Gnomad4 OTH AF: 0.116

Alfa AF: 0.111 Hom.: 235

Bravo AF: 0.115

Asia WGS AF: 0.180 AC: 624 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

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, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 02, 2017	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.30
DANN	Benign	0.75

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: rs2270916; hg19: chr3-122001099; COSMIC: COSV56138050;