3-122208898-G-A

Variant names:

• chr3-122208898-G-A
• rs17203502
• NM_000388.4:c.-243+25086G>A

Variant summary

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

The NM_000388.4(CASR):​c.-243+25086G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.481 in 151,952 control chromosomes in the GnomAD database, including 18,468 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 0.48 (18468 hom., cov: 32)
• Consequence: CASR NM_000388.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.84
• Publications: 5 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, ClinGen, Labcorp Genetics (formerly Invitae)
• familial hypocalciuric hypercalcemia 1

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

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, 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=-0.97).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.568 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASR	NM_000388.4	MANE Select	c.-243+25086G>A		intron	N/A	NP_000379.3
	CASR	NM_001178065.2		c.-243+24369G>A		intron	N/A	NP_001171536.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASR	ENST00000639785.2	TSL:1 MANE Select	c.-243+25086G>A		intron	N/A	ENSP00000491584.2
	CASR	ENST00000498619.4	TSL:1	c.-243+24369G>A		intron	N/A	ENSP00000420194.1
	CASR	ENST00000638421.1	TSL:5	c.-243+24369G>A		intron	N/A	ENSP00000492190.1

Frequencies

GnomAD3 genomes AF: 0.481 AC: 73037 AN: 151832 Hom.: 18450 Cov.: 32

Gnomad AFR AF: 0.574

Gnomad AMI AF: 0.525

Gnomad AMR AF: 0.394

Gnomad ASJ AF: 0.543

Gnomad EAS AF: 0.0625

Gnomad SAS AF: 0.254

Gnomad FIN AF: 0.482

Gnomad MID AF: 0.500

Gnomad NFE AF: 0.488

Gnomad OTH AF: 0.482

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

GnomAD4 genome AF: 0.481 AC: 73082 AN: 151952 Hom.: 18468 Cov.: 32 AF XY: 0.476 AC XY: 35356 AN XY: 74316

African (AFR) AF: 0.574 AC: 23762 AN: 41396

American (AMR) AF: 0.393 AC: 6001 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.543 AC: 1882 AN: 3468

East Asian (EAS) AF: 0.0625 AC: 323 AN: 5172

South Asian (SAS) AF: 0.253 AC: 1218 AN: 4812

European-Finnish (FIN) AF: 0.482 AC: 5095 AN: 10562

Middle Eastern (MID) AF: 0.520 AC: 153 AN: 294

European-Non Finnish (NFE) AF: 0.488 AC: 33166 AN: 67954

Other (OTH) AF: 0.475 AC: 1005 AN: 2114

Alfa AF: 0.496 Hom.: 2821

Bravo AF: 0.480

Asia WGS AF: 0.184 AC: 644 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.026
DANN	Benign	0.64
PhyloP100		-1.8
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: rs17203502; hg19: chr3-121927745;