rs3804593

Positions:

• chr3-122265174-G-A

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	UniProt
CASR	NM_000388.4	c.1377+2762G>A		intron_variant		ENST00000639785.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CASR	ENST00000639785.2	c.1377+2762G>A		intron_variant		1	NM_000388.4	P1
CASR	ENST00000498619.4	c.1377+2762G>A		intron_variant		1
CASR	ENST00000490131.7	c.1377+2762G>A		intron_variant		5
CASR	ENST00000638421.1	c.1377+2762G>A		intron_variant		5		P1

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

Gnomad4 AFR AF: 0.246

Gnomad4 AMR AF: 0.115

Gnomad4 ASJ AF: 0.0825

Gnomad4 EAS AF: 0.398

Gnomad4 SAS AF: 0.0732

Gnomad4 FIN AF: 0.129

Gnomad4 NFE AF: 0.134

Gnomad4 OTH AF: 0.151

Alfa AF: 0.134 Hom.: 1498

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

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

Publications

LitVar

Other links and lift over

dbSNP: rs3804593; hg19: chr3-121984021;