chr3-122257685-A-T

Position:

• chr3-122257685-A-T

Variant summary

Our verdict is Benign. Variant got -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

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=-0.79).
• 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/exons	MANE	UniProt
CASR	NM_000388.4	c.492+298A>T		intron_variant		ENST00000639785.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CASR	ENST00000639785.2	c.492+298A>T		intron_variant		1	NM_000388.4	P1

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

Gnomad4 AFR exome AF: 0.419

Gnomad4 AMR exome AF: 0.324

Gnomad4 ASJ exome AF: 0.343

Gnomad4 EAS exome AF: 0.404

Gnomad4 SAS exome AF: 0.308

Gnomad4 FIN exome AF: 0.504

Gnomad4 NFE exome AF: 0.492

Gnomad4 OTH exome AF: 0.430

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

Gnomad4 AFR AF: 0.423

Gnomad4 AMR AF: 0.343

Gnomad4 ASJ AF: 0.349

Gnomad4 EAS AF: 0.400

Gnomad4 SAS AF: 0.284

Gnomad4 FIN AF: 0.504

Gnomad4 NFE AF: 0.491

Gnomad4 OTH AF: 0.436

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

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

Publications

LitVar

Other links and lift over

dbSNP: rs3749204; hg19: chr3-121976532;