rs2134225

Variant names:

• chr3-122283406-A-C
• rs2134225
• NM_000388.4:c.1733-281A>C

Your query was ambiguous. Multiple possible variants found:

• chr3-122283406-A-C
• chr3-122283406-A-G
• chr3-122283406-A-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.1733-281A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.922 in 152,232 control chromosomes in the GnomAD database, including 64,954 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 0.92 (64954 hom., cov: 33)
• Consequence: CASR NM_000388.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.38
• Publications: 4 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=-0.94).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.959 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASR	NM_000388.4	c.1733-281A>C		intron_variant	Intron 6 of 6	ENST00000639785.2	NP_000379.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CASR	ENST00000639785.2	c.1733-281A>C		intron_variant	Intron 6 of 6	1	NM_000388.4	ENSP00000491584.2
CASR	ENST00000498619.4	c.1763-281A>C		intron_variant	Intron 6 of 6	1		ENSP00000420194.1
CASR	ENST00000638421.1	c.1733-281A>C		intron_variant	Intron 6 of 6	5		ENSP00000492190.1
CASR	ENST00000490131.7	c.1502-281A>C		intron_variant	Intron 4 of 4	5		ENSP00000418685.2

Frequencies

GnomAD3 genomes AF: 0.922 AC: 140201 AN: 152114 Hom.: 64912 Cov.: 33

Gnomad AFR AF: 0.826

Gnomad AMI AF: 0.946

Gnomad AMR AF: 0.969

Gnomad ASJ AF: 0.984

Gnomad EAS AF: 0.981

Gnomad SAS AF: 0.956

Gnomad FIN AF: 0.917

Gnomad MID AF: 0.975

Gnomad NFE AF: 0.959

Gnomad OTH AF: 0.939

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

GnomAD4 genome AF: 0.922 AC: 140301 AN: 152232 Hom.: 64954 Cov.: 33 AF XY: 0.923 AC XY: 68667 AN XY: 74422

African (AFR) AF: 0.826 AC: 34288 AN: 41516

American (AMR) AF: 0.969 AC: 14834 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.984 AC: 3415 AN: 3472

East Asian (EAS) AF: 0.981 AC: 5086 AN: 5184

South Asian (SAS) AF: 0.956 AC: 4610 AN: 4822

European-Finnish (FIN) AF: 0.917 AC: 9710 AN: 10584

Middle Eastern (MID) AF: 0.973 AC: 284 AN: 292

European-Non Finnish (NFE) AF: 0.959 AC: 65224 AN: 68028

Other (OTH) AF: 0.940 AC: 1987 AN: 2114

Alfa AF: 0.948 Hom.: 35530

Bravo AF: 0.923

Asia WGS AF: 0.954 AC: 3319 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.85
DANN	Benign	0.68
PhyloP100		-2.4
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: rs2134225; hg19: chr3-122002253;