3-122257685-A-T

Variant names:

• chr3-122257685-A-T
• rs3749204
• NM_000388.4:c.492+298A>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.492+298A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.449 in 278,364 control chromosomes in the GnomAD database, including 29,118 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 0.45 (15354 hom., cov: 32)
  • Exomes 𝑓: 0.45 (13764 hom.)
• Consequence: CASR NM_000388.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.363
• Publications: 2 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=-0.79).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.486 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASR	NM_000388.4	c.492+298A>T		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.492+298A>T		intron_variant	Intron 3 of 6	1	NM_000388.4	ENSP00000491584.2

Frequencies

GnomAD3 genomes AF: 0.446 AC: 67534 AN: 151462 Hom.: 15357 Cov.: 32

Gnomad AFR AF: 0.423

Gnomad AMI AF: 0.687

Gnomad AMR AF: 0.344

Gnomad ASJ AF: 0.349

Gnomad EAS AF: 0.400

Gnomad SAS AF: 0.285

Gnomad FIN AF: 0.504

Gnomad MID AF: 0.430

Gnomad NFE AF: 0.491

Gnomad OTH AF: 0.440

GnomAD4 exome AF: 0.453 AC: 57492 AN: 126784 Hom.: 13764 Cov.: 0 AF XY: 0.447 AC XY: 29006 AN XY: 64834

African (AFR) AF: 0.419 AC: 1792 AN: 4274

American (AMR) AF: 0.324 AC: 1896 AN: 5854

Ashkenazi Jewish (ASJ) AF: 0.343 AC: 1511 AN: 4410

East Asian (EAS) AF: 0.404 AC: 3674 AN: 9102

South Asian (SAS) AF: 0.308 AC: 2810 AN: 9116

European-Finnish (FIN) AF: 0.504 AC: 3230 AN: 6410

Middle Eastern (MID) AF: 0.388 AC: 229 AN: 590

European-Non Finnish (NFE) AF: 0.492 AC: 38968 AN: 79154

Other (OTH) AF: 0.430 AC: 3382 AN: 7874

GnomAD4 genome AF: 0.446 AC: 67534 AN: 151580 Hom.: 15354 Cov.: 32 AF XY: 0.442 AC XY: 32714 AN XY: 74026

African (AFR) AF: 0.423 AC: 17446 AN: 41280

American (AMR) AF: 0.343 AC: 5235 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.349 AC: 1209 AN: 3464

East Asian (EAS) AF: 0.400 AC: 2069 AN: 5174

South Asian (SAS) AF: 0.284 AC: 1368 AN: 4810

European-Finnish (FIN) AF: 0.504 AC: 5282 AN: 10472

Middle Eastern (MID) AF: 0.404 AC: 118 AN: 292

European-Non Finnish (NFE) AF: 0.491 AC: 33273 AN: 67832

Other (OTH) AF: 0.436 AC: 914 AN: 2098

Alfa AF: 0.449 Hom.: 1868

Bravo AF: 0.436

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	2.5
DANN	Benign	0.85
PhyloP100		-0.36
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs3749204; hg19: chr3-121976532;