3-122227252-A-G

Variant names:

• chr3-122227252-A-G
• rs7627468
• NM_000388.4:c.-242-26696A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000388.4(CASR):​c.-242-26696A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.739 in 151,954 control chromosomes in the GnomAD database, including 41,679 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.74 (41679 hom., cov: 32)
• Consequence: CASR NM_000388.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.41
• Publications: 13 publications found

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 Gene-Disease associations (from GenCC):

• autosomal dominant hypocalcemia 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Illumina, Labcorp Genetics (formerly Invitae), ClinGen
• familial hypocalciuric hypercalcemia 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Illumina, Orphanet, ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• neonatal severe primary hyperparathyroidism

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)
• autosomal dominant hypocalcemia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• epilepsy, idiopathic generalized, susceptibility to, 8

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
• epilepsy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.04).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.814 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000388.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASR	NM_000388.4	MANE Select	c.-242-26696A>G		intron	N/A	NP_000379.3
	CASR	NM_001178065.2		c.-242-26696A>G		intron	N/A	NP_001171536.2	P41180-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASR	ENST00000639785.2	TSL:1 MANE Select	c.-242-26696A>G		intron	N/A	ENSP00000491584.2	P41180-1
	CASR	ENST00000498619.4	TSL:1	c.-242-26696A>G		intron	N/A	ENSP00000420194.1	P41180-2
	CASR	ENST00000638421.1	TSL:5	c.-242-26696A>G		intron	N/A	ENSP00000492190.1	P41180-1

Frequencies

GnomAD3 genomes AF: 0.739 AC: 112206 AN: 151834 Hom.: 41647 Cov.: 32

Gnomad AFR AF: 0.741

Gnomad AMI AF: 0.843

Gnomad AMR AF: 0.826

Gnomad ASJ AF: 0.762

Gnomad EAS AF: 0.472

Gnomad SAS AF: 0.629

Gnomad FIN AF: 0.695

Gnomad MID AF: 0.764

Gnomad NFE AF: 0.750

Gnomad OTH AF: 0.753

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.739 AC: 112293 AN: 151954 Hom.: 41679 Cov.: 32 AF XY: 0.738 AC XY: 54827 AN XY: 74268

African (AFR) AF: 0.741 AC: 30767 AN: 41520

American (AMR) AF: 0.826 AC: 12645 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.762 AC: 2644 AN: 3472

East Asian (EAS) AF: 0.472 AC: 2404 AN: 5092

South Asian (SAS) AF: 0.629 AC: 3012 AN: 4792

European-Finnish (FIN) AF: 0.695 AC: 7342 AN: 10566

Middle Eastern (MID) AF: 0.771 AC: 225 AN: 292

European-Non Finnish (NFE) AF: 0.750 AC: 50920 AN: 67908

Other (OTH) AF: 0.746 AC: 1569 AN: 2104

Alfa AF: 0.678 Hom.: 2395

Bravo AF: 0.750

Asia WGS AF: 0.540 AC: 1880 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.6
DANN	Benign	0.15
PhyloP100		-1.4
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs7627468; hg19: chr3-121946099; COSMIC: COSV72229371;