rs937626

Variant names:

• chr3-122252955-G-A
• rs937626
• NM_000388.4:c.-242-993G>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.-242-993G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.665 in 151,988 control chromosomes in the GnomAD database, including 33,966 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 0.67 (33966 hom., cov: 31)
• Consequence: CASR NM_000388.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.410
• Publications: 6 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=-0.98).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.765 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASR	NM_000388.4	c.-242-993G>A		intron_variant	Intron 1 of 6	ENST00000639785.2	NP_000379.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CASR	ENST00000639785.2	c.-242-993G>A		intron_variant	Intron 1 of 6	1	NM_000388.4	ENSP00000491584.2
CASR	ENST00000498619.4	c.-242-993G>A		intron_variant	Intron 1 of 6	1		ENSP00000420194.1
CASR	ENST00000638421.1	c.-242-993G>A		intron_variant	Intron 1 of 6	5		ENSP00000492190.1

Frequencies

GnomAD3 genomes AF: 0.665 AC: 101056 AN: 151870 Hom.: 33950 Cov.: 31

Gnomad AFR AF: 0.618

Gnomad AMI AF: 0.741

Gnomad AMR AF: 0.776

Gnomad ASJ AF: 0.684

Gnomad EAS AF: 0.448

Gnomad SAS AF: 0.537

Gnomad FIN AF: 0.659

Gnomad MID AF: 0.715

Gnomad NFE AF: 0.694

Gnomad OTH AF: 0.675

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

GnomAD4 genome AF: 0.665 AC: 101122 AN: 151988 Hom.: 33966 Cov.: 31 AF XY: 0.666 AC XY: 49483 AN XY: 74268

African (AFR) AF: 0.618 AC: 25588 AN: 41428

American (AMR) AF: 0.776 AC: 11867 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.684 AC: 2375 AN: 3470

East Asian (EAS) AF: 0.449 AC: 2312 AN: 5150

South Asian (SAS) AF: 0.537 AC: 2584 AN: 4812

European-Finnish (FIN) AF: 0.659 AC: 6958 AN: 10558

Middle Eastern (MID) AF: 0.721 AC: 212 AN: 294

European-Non Finnish (NFE) AF: 0.694 AC: 47137 AN: 67962

Other (OTH) AF: 0.668 AC: 1413 AN: 2116

Alfa AF: 0.681 Hom.: 4543

Bravo AF: 0.673

Asia WGS AF: 0.488 AC: 1698 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.62
DANN	Benign	0.67
PhyloP100		-0.41
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: rs937626; hg19: chr3-121971802;