NM_000388.4:c.493-1146G>A

Variant names:

• chr3-122260382-G-A
• rs3804592
• NM_000388.4:c.493-1146G>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.493-1146G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.178 in 152,222 control chromosomes in the GnomAD database, including 2,783 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 0.18 (2783 hom., cov: 32)
• Consequence: CASR NM_000388.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.232
• Publications: 15 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=-0.96).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.251 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASR	NM_000388.4	c.493-1146G>A		intron_variant	Intron 3 of 6	ENST00000639785.2	NP_000379.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CASR	ENST00000639785.2	c.493-1146G>A		intron_variant	Intron 3 of 6	1	NM_000388.4	ENSP00000491584.2
CASR	ENST00000498619.4	c.493-1146G>A		intron_variant	Intron 3 of 6	1		ENSP00000420194.1
CASR	ENST00000638421.1	c.493-1146G>A		intron_variant	Intron 3 of 6	5		ENSP00000492190.1
CASR	ENST00000490131.7	c.493-1146G>A		intron_variant	Intron 2 of 4	5		ENSP00000418685.2

Frequencies

GnomAD3 genomes AF: 0.178 AC: 27032 AN: 152104 Hom.: 2777 Cov.: 32

Gnomad AFR AF: 0.255

Gnomad AMI AF: 0.0943

Gnomad AMR AF: 0.246

Gnomad ASJ AF: 0.126

Gnomad EAS AF: 0.0277

Gnomad SAS AF: 0.159

Gnomad FIN AF: 0.111

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.143

Gnomad OTH AF: 0.156

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

GnomAD4 genome AF: 0.178 AC: 27072 AN: 152222 Hom.: 2783 Cov.: 32 AF XY: 0.177 AC XY: 13195 AN XY: 74436

African (AFR) AF: 0.255 AC: 10591 AN: 41492

American (AMR) AF: 0.247 AC: 3778 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.126 AC: 436 AN: 3470

East Asian (EAS) AF: 0.0277 AC: 144 AN: 5194

South Asian (SAS) AF: 0.158 AC: 764 AN: 4830

European-Finnish (FIN) AF: 0.111 AC: 1182 AN: 10606

Middle Eastern (MID) AF: 0.0952 AC: 28 AN: 294

European-Non Finnish (NFE) AF: 0.143 AC: 9730 AN: 68004

Other (OTH) AF: 0.157 AC: 333 AN: 2116

Alfa AF: 0.154 Hom.: 8457

Bravo AF: 0.192

Asia WGS AF: 0.139 AC: 482 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.71
DANN	Benign	0.60
PhyloP100		-0.23
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: rs3804592; hg19: chr3-121979229;