NM_000388.4:c.493-685G>A

Variant names:

• chr3-122260843-G-A
• rs12485716
• NM_000388.4:c.493-685G>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.493-685G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.355 in 152,062 control chromosomes in the GnomAD database, including 10,623 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 0.35 (10623 hom., cov: 32)
• Consequence: CASR NM_000388.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.650
• Publications: 16 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=-0.86).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.52 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASR	NM_000388.4	c.493-685G>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.493-685G>A		intron_variant	Intron 3 of 6	1	NM_000388.4	ENSP00000491584.2
CASR	ENST00000498619.4	c.493-685G>A		intron_variant	Intron 3 of 6	1		ENSP00000420194.1
CASR	ENST00000638421.1	c.493-685G>A		intron_variant	Intron 3 of 6	5		ENSP00000492190.1
CASR	ENST00000490131.7	c.493-685G>A		intron_variant	Intron 2 of 4	5		ENSP00000418685.2

Frequencies

GnomAD3 genomes AF: 0.354 AC: 53835 AN: 151944 Hom.: 10604 Cov.: 32

Gnomad AFR AF: 0.526

Gnomad AMI AF: 0.401

Gnomad AMR AF: 0.363

Gnomad ASJ AF: 0.208

Gnomad EAS AF: 0.427

Gnomad SAS AF: 0.233

Gnomad FIN AF: 0.239

Gnomad MID AF: 0.209

Gnomad NFE AF: 0.278

Gnomad OTH AF: 0.314

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

GnomAD4 genome AF: 0.355 AC: 53910 AN: 152062 Hom.: 10623 Cov.: 32 AF XY: 0.353 AC XY: 26256 AN XY: 74342

African (AFR) AF: 0.526 AC: 21802 AN: 41430

American (AMR) AF: 0.363 AC: 5546 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.208 AC: 722 AN: 3470

East Asian (EAS) AF: 0.427 AC: 2212 AN: 5180

South Asian (SAS) AF: 0.231 AC: 1113 AN: 4808

European-Finnish (FIN) AF: 0.239 AC: 2534 AN: 10584

Middle Eastern (MID) AF: 0.231 AC: 68 AN: 294

European-Non Finnish (NFE) AF: 0.278 AC: 18883 AN: 67996

Other (OTH) AF: 0.316 AC: 664 AN: 2104

Alfa AF: 0.296 Hom.: 4544

Bravo AF: 0.375

Asia WGS AF: 0.341 AC: 1187 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	7.9
DANN	Benign	0.78
PhyloP100		0.65
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: rs12485716; hg19: chr3-121979690;