rs1501899

Variant names:

• chr3-122188481-A-G
• rs1501899
• NM_000388.4:c.-243+4669A>G

Your query was ambiguous. Multiple possible variants found:

• chr3-122188481-A-G
• chr3-122188481-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.-243+4669A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.616 in 150,830 control chromosomes in the GnomAD database, including 28,765 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 0.62 (28765 hom., cov: 31)
• Consequence: CASR NM_000388.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.925
• Publications: 18 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=-0.82).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.729 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASR	NM_000388.4	c.-243+4669A>G		intron_variant	Intron 1 of 6	ENST00000639785.2	NP_000379.3
CASR	NM_001178065.2	c.-243+3952A>G		intron_variant	Intron 1 of 6		NP_001171536.2
CASR	XM_006713789.4	c.-243+3952A>G		intron_variant	Intron 1 of 6		XP_006713852.1
CASR	XM_047449065.1	c.-419+3952A>G		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.-243+4669A>G		intron_variant	Intron 1 of 6	1	NM_000388.4	ENSP00000491584.2
CASR	ENST00000498619.4	c.-243+3952A>G		intron_variant	Intron 1 of 6	1		ENSP00000420194.1
CASR	ENST00000638421.1	c.-243+3952A>G		intron_variant	Intron 1 of 6	5		ENSP00000492190.1
CASR	ENST00000643573.1	n.98+3952A>G		intron_variant	Intron 1 of 2

Frequencies

GnomAD3 genomes AF: 0.616 AC: 92836 AN: 150718 Hom.: 28735 Cov.: 31

Gnomad AFR AF: 0.587

Gnomad AMI AF: 0.664

Gnomad AMR AF: 0.740

Gnomad ASJ AF: 0.630

Gnomad EAS AF: 0.375

Gnomad SAS AF: 0.468

Gnomad FIN AF: 0.579

Gnomad MID AF: 0.668

Gnomad NFE AF: 0.638

Gnomad OTH AF: 0.634

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

GnomAD4 genome AF: 0.616 AC: 92912 AN: 150830 Hom.: 28765 Cov.: 31 AF XY: 0.615 AC XY: 45360 AN XY: 73758

African (AFR) AF: 0.587 AC: 24016 AN: 40922

American (AMR) AF: 0.741 AC: 11273 AN: 15216

Ashkenazi Jewish (ASJ) AF: 0.630 AC: 2176 AN: 3452

East Asian (EAS) AF: 0.375 AC: 1942 AN: 5178

South Asian (SAS) AF: 0.469 AC: 2222 AN: 4740

European-Finnish (FIN) AF: 0.579 AC: 6050 AN: 10446

Middle Eastern (MID) AF: 0.663 AC: 195 AN: 294

European-Non Finnish (NFE) AF: 0.638 AC: 43115 AN: 67572

Other (OTH) AF: 0.628 AC: 1319 AN: 2100

Alfa AF: 0.614 Hom.: 3723

Bravo AF: 0.626

Asia WGS AF: 0.393 AC: 1369 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	4.5
DANN	Benign	0.80
PhyloP100		0.93
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: rs1501899; hg19: chr3-121907328;