rs9866419

Variant names:

• chr3-122221362-G-A
• rs9866419
• NM_000388.4:c.-242-32586G>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.-242-32586G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.68 in 151,942 control chromosomes in the GnomAD database, including 35,378 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 0.68 (35378 hom., cov: 31)
• Consequence: CASR NM_000388.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0390
• Publications: 7 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=-0.88).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.775 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASR	NM_000388.4	c.-242-32586G>A		intron_variant	Intron 1 of 6	ENST00000639785.2	NP_000379.3
CASR	NM_001178065.2	c.-242-32586G>A		intron_variant	Intron 1 of 6		NP_001171536.2
CASR	XM_006713789.4	c.-242-32586G>A		intron_variant	Intron 1 of 6		XP_006713852.1
CASR	XM_047449065.1	c.-418-32586G>A		intron_variant	Intron 1 of 5		XP_047305021.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CASR	ENST00000639785.2	c.-242-32586G>A		intron_variant	Intron 1 of 6	1	NM_000388.4	ENSP00000491584.2
CASR	ENST00000498619.4	c.-242-32586G>A		intron_variant	Intron 1 of 6	1		ENSP00000420194.1
CASR	ENST00000638421.1	c.-242-32586G>A		intron_variant	Intron 1 of 6	5		ENSP00000492190.1
CASR	ENST00000643573.1	n.99-24016G>A		intron_variant	Intron 1 of 2

Frequencies

GnomAD3 genomes AF: 0.680 AC: 103199 AN: 151824 Hom.: 35362 Cov.: 31

Gnomad AFR AF: 0.634

Gnomad AMI AF: 0.742

Gnomad AMR AF: 0.787

Gnomad ASJ AF: 0.703

Gnomad EAS AF: 0.452

Gnomad SAS AF: 0.571

Gnomad FIN AF: 0.662

Gnomad MID AF: 0.718

Gnomad NFE AF: 0.709

Gnomad OTH AF: 0.689

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

GnomAD4 genome AF: 0.680 AC: 103265 AN: 151942 Hom.: 35378 Cov.: 31 AF XY: 0.680 AC XY: 50528 AN XY: 74254

African (AFR) AF: 0.634 AC: 26246 AN: 41392

American (AMR) AF: 0.787 AC: 12025 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.703 AC: 2438 AN: 3470

East Asian (EAS) AF: 0.453 AC: 2337 AN: 5158

South Asian (SAS) AF: 0.572 AC: 2749 AN: 4810

European-Finnish (FIN) AF: 0.662 AC: 6988 AN: 10548

Middle Eastern (MID) AF: 0.724 AC: 213 AN: 294

European-Non Finnish (NFE) AF: 0.708 AC: 48152 AN: 67966

Other (OTH) AF: 0.681 AC: 1440 AN: 2114

Alfa AF: 0.686 Hom.: 5007

Bravo AF: 0.688

Asia WGS AF: 0.479 AC: 1668 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	5.8
DANN	Benign	0.72
PhyloP100		-0.039
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: rs9866419; hg19: chr3-121940209;