rs4678174

Positions:

• chr3-122282024-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000388.4(CASR):​c.1609-89C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.656 in 1,586,760 control chromosomes in the GnomAD database, including 348,569 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.56 (26503 hom., cov: 32)
  • Exomes 𝑓: 0.67 (322066 hom.)
• Consequence: CASR NM_000388.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.368

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 3-122282024-C-T is Benign according to our data. Variant chr3-122282024-C-T is described in ClinVar as [Benign]. Clinvar id is 1192651.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-122282024-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.704 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CASR	NM_000388.4	c.1609-89C>T		intron_variant		ENST00000639785.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CASR	ENST00000639785.2	c.1609-89C>T		intron_variant		1	NM_000388.4	P1
CASR	ENST00000498619.4	c.1609-59C>T		intron_variant		1
CASR	ENST00000490131.7	c.1378-89C>T		intron_variant		5
CASR	ENST00000638421.1	c.1609-89C>T		intron_variant		5		P1

Frequencies

GnomAD3 genomes AF: 0.563 AC: 85609 AN: 151978 Hom.: 26505 Cov.: 32

Gnomad AFR AF: 0.285

Gnomad AMI AF: 0.545

Gnomad AMR AF: 0.605

Gnomad ASJ AF: 0.775

Gnomad EAS AF: 0.557

Gnomad SAS AF: 0.722

Gnomad FIN AF: 0.677

Gnomad MID AF: 0.763

Gnomad NFE AF: 0.681

Gnomad OTH AF: 0.625

GnomAD4 exome AF: 0.665 AC: 954660 AN: 1434662 Hom.: 322066 AF XY: 0.671 AC XY: 477952 AN XY: 712644

Gnomad4 AFR exome AF: 0.273

Gnomad4 AMR exome AF: 0.572

Gnomad4 ASJ exome AF: 0.773

Gnomad4 EAS exome AF: 0.566

Gnomad4 SAS exome AF: 0.739

Gnomad4 FIN exome AF: 0.679

Gnomad4 NFE exome AF: 0.675

Gnomad4 OTH exome AF: 0.668

GnomAD4 genome AF: 0.563 AC: 85631 AN: 152098 Hom.: 26503 Cov.: 32 AF XY: 0.566 AC XY: 42040 AN XY: 74340

Gnomad4 AFR AF: 0.285

Gnomad4 AMR AF: 0.605

Gnomad4 ASJ AF: 0.775

Gnomad4 EAS AF: 0.557

Gnomad4 SAS AF: 0.724

Gnomad4 FIN AF: 0.677

Gnomad4 NFE AF: 0.681

Gnomad4 OTH AF: 0.623

Alfa AF: 0.606 Hom.: 5828

Bravo AF: 0.544

Asia WGS AF: 0.611 AC: 2124 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Autosomal dominant hypocalcemia 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Familial hypocalciuric hypercalcemia 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Neonatal severe primary hyperparathyroidism Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	6.9
DANN	Benign	0.76

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: rs4678174; hg19: chr3-122000871; COSMIC: COSV56139987;