3-122214658-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000388.4(CASR):c.-243+30846A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.725 in 152,028 control chromosomes in the GnomAD database, including 40,170 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 0.72 (40170 hom., cov: 31)
• Consequence: CASR NM_000388.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0660

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=-0.92).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.808 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CASR	NM_000388.4	c.-243+30846A>G		intron_variant		ENST00000639785.2
CASR	NM_001178065.2	c.-243+30129A>G		intron_variant
CASR	XM_006713789.4	c.-243+30129A>G		intron_variant
CASR	XM_047449065.1	c.-419+30129A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CASR	ENST00000639785.2	c.-243+30846A>G		intron_variant		1	NM_000388.4	P1
CASR	ENST00000498619.4	c.-243+30129A>G		intron_variant		1
CASR	ENST00000638421.1	c.-243+30129A>G		intron_variant		5		P1
CASR	ENST00000643573.1	n.98+30129A>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.725 AC: 110100 AN: 151910 Hom.: 40142 Cov.: 31

Gnomad AFR AF: 0.674

Gnomad AMI AF: 0.834

Gnomad AMR AF: 0.820

Gnomad ASJ AF: 0.765

Gnomad EAS AF: 0.465

Gnomad SAS AF: 0.648

Gnomad FIN AF: 0.734

Gnomad MID AF: 0.753

Gnomad NFE AF: 0.754

Gnomad OTH AF: 0.739

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

GnomAD4 genome AF: 0.725 AC: 110178 AN: 152028 Hom.: 40170 Cov.: 31 AF XY: 0.727 AC XY: 54008 AN XY: 74330

Gnomad4 AFR AF: 0.674

Gnomad4 AMR AF: 0.820

Gnomad4 ASJ AF: 0.765

Gnomad4 EAS AF: 0.466

Gnomad4 SAS AF: 0.648

Gnomad4 FIN AF: 0.734

Gnomad4 NFE AF: 0.754

Gnomad4 OTH AF: 0.731

Alfa AF: 0.740 Hom.: 6979

Bravo AF: 0.731

Asia WGS AF: 0.543 AC: 1890 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
Cadd	Benign	2.0
Dann	Benign	0.50

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

Publications

LitVar

Other links and lift over

dbSNP: rs6438712; hg19: chr3-121933505;