rs3804593

Variant names:

• chr3-122265174-G-A
• rs3804593
• NM_000388.4:c.1377+2762G>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.1377+2762G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.169 in 152,034 control chromosomes in the GnomAD database, including 2,619 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 0.17 (2619 hom., cov: 32)
• Consequence: CASR NM_000388.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.389
• 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=-0.85).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.384 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASR	NM_000388.4	c.1377+2762G>A		intron_variant	Intron 4 of 6	ENST00000639785.2	NP_000379.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CASR	ENST00000639785.2	c.1377+2762G>A		intron_variant	Intron 4 of 6	1	NM_000388.4	ENSP00000491584.2
CASR	ENST00000498619.4	c.1377+2762G>A		intron_variant	Intron 4 of 6	1		ENSP00000420194.1
CASR	ENST00000638421.1	c.1377+2762G>A		intron_variant	Intron 4 of 6	5		ENSP00000492190.1
CASR	ENST00000490131.7	c.1377+2762G>A		intron_variant	Intron 3 of 4	5		ENSP00000418685.2

Frequencies

GnomAD3 genomes AF: 0.170 AC: 25750 AN: 151916 Hom.: 2617 Cov.: 32

Gnomad AFR AF: 0.246

Gnomad AMI AF: 0.308

Gnomad AMR AF: 0.115

Gnomad ASJ AF: 0.0825

Gnomad EAS AF: 0.399

Gnomad SAS AF: 0.0732

Gnomad FIN AF: 0.129

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.134

Gnomad OTH AF: 0.151

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

GnomAD4 genome AF: 0.169 AC: 25764 AN: 152034 Hom.: 2619 Cov.: 32 AF XY: 0.169 AC XY: 12560 AN XY: 74322

African (AFR) AF: 0.246 AC: 10173 AN: 41432

American (AMR) AF: 0.115 AC: 1754 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0825 AC: 286 AN: 3466

East Asian (EAS) AF: 0.398 AC: 2064 AN: 5184

South Asian (SAS) AF: 0.0732 AC: 352 AN: 4808

European-Finnish (FIN) AF: 0.129 AC: 1363 AN: 10570

Middle Eastern (MID) AF: 0.129 AC: 38 AN: 294

European-Non Finnish (NFE) AF: 0.134 AC: 9136 AN: 67972

Other (OTH) AF: 0.151 AC: 318 AN: 2104

Alfa AF: 0.139 Hom.: 2102

Bravo AF: 0.175

Asia WGS AF: 0.191 AC: 666 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	5.2
DANN	Benign	0.62
PhyloP100		0.39
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: rs3804593; hg19: chr3-121984021;