NM_000388.4:c.-242-18491A>T

Variant names:

• chr3-122235457-A-T
• rs9874845
• NM_000388.4:c.-242-18491A>T

Variant summary

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

The NM_000388.4(CASR):​c.-242-18491A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.668 in 152,120 control chromosomes in the GnomAD database, including 34,209 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 (34209 hom., cov: 33)
• Consequence: CASR NM_000388.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.254
• Publications: 1 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=-0.83).
• 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.-242-18491A>T		intron_variant	Intron 1 of 6	ENST00000639785.2	NP_000379.3
CASR	NM_001178065.2	c.-242-18491A>T		intron_variant	Intron 1 of 6		NP_001171536.2
CASR	XM_006713789.4	c.-242-18491A>T		intron_variant	Intron 1 of 6		XP_006713852.1
CASR	XM_047449065.1	c.-418-18491A>T		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.-242-18491A>T		intron_variant	Intron 1 of 6	1	NM_000388.4	ENSP00000491584.2
CASR	ENST00000498619.4	c.-242-18491A>T		intron_variant	Intron 1 of 6	1		ENSP00000420194.1
CASR	ENST00000638421.1	c.-242-18491A>T		intron_variant	Intron 1 of 6	5		ENSP00000492190.1
CASR	ENST00000643573.1	n.99-9921A>T		intron_variant	Intron 1 of 2

Frequencies

GnomAD3 genomes AF: 0.668 AC: 101531 AN: 152000 Hom.: 34198 Cov.: 33

Gnomad AFR AF: 0.626

Gnomad AMI AF: 0.740

Gnomad AMR AF: 0.776

Gnomad ASJ AF: 0.685

Gnomad EAS AF: 0.450

Gnomad SAS AF: 0.539

Gnomad FIN AF: 0.658

Gnomad MID AF: 0.708

Gnomad NFE AF: 0.694

Gnomad OTH AF: 0.676

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

GnomAD4 genome AF: 0.668 AC: 101584 AN: 152120 Hom.: 34209 Cov.: 33 AF XY: 0.668 AC XY: 49703 AN XY: 74366

African (AFR) AF: 0.625 AC: 25935 AN: 41490

American (AMR) AF: 0.777 AC: 11881 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.685 AC: 2377 AN: 3470

East Asian (EAS) AF: 0.451 AC: 2329 AN: 5164

South Asian (SAS) AF: 0.539 AC: 2599 AN: 4822

European-Finnish (FIN) AF: 0.658 AC: 6966 AN: 10580

Middle Eastern (MID) AF: 0.712 AC: 208 AN: 292

European-Non Finnish (NFE) AF: 0.694 AC: 47204 AN: 67986

Other (OTH) AF: 0.668 AC: 1413 AN: 2114

Alfa AF: 0.683 Hom.: 4406

Bravo AF: 0.677

Asia WGS AF: 0.471 AC: 1641 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	4.9
DANN	Benign	0.69
PhyloP100		0.25
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: rs9874845; hg19: chr3-121954304;