rs35780274

Variant names:

• chr3-122274627-C-T
• rs35780274
• NM_000388.4:c.1378-1185C>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.1378-1185C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.349 in 152,030 control chromosomes in the GnomAD database, including 10,611 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 (10611 hom., cov: 32)
• Consequence: CASR NM_000388.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.635
• Publications: 4 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=-0.98).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.449 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASR	NM_000388.4	c.1378-1185C>T		intron_variant	Intron 4 of 6	ENST00000639785.2	NP_000379.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CASR	ENST00000639785.2	c.1378-1185C>T		intron_variant	Intron 4 of 6	1	NM_000388.4	ENSP00000491584.2
CASR	ENST00000498619.4	c.1378-1185C>T		intron_variant	Intron 4 of 6	1		ENSP00000420194.1
CASR	ENST00000638421.1	c.1378-1185C>T		intron_variant	Intron 4 of 6	5		ENSP00000492190.1
CASR	ENST00000490131.7	c.1378-7486C>T		intron_variant	Intron 3 of 4	5		ENSP00000418685.2

Frequencies

GnomAD3 genomes AF: 0.349 AC: 53044 AN: 151912 Hom.: 10621 Cov.: 32

Gnomad AFR AF: 0.191

Gnomad AMI AF: 0.479

Gnomad AMR AF: 0.314

Gnomad ASJ AF: 0.511

Gnomad EAS AF: 0.0187

Gnomad SAS AF: 0.353

Gnomad FIN AF: 0.433

Gnomad MID AF: 0.513

Gnomad NFE AF: 0.453

Gnomad OTH AF: 0.395

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

GnomAD4 genome AF: 0.349 AC: 53030 AN: 152030 Hom.: 10611 Cov.: 32 AF XY: 0.345 AC XY: 25638 AN XY: 74294

African (AFR) AF: 0.191 AC: 7904 AN: 41468

American (AMR) AF: 0.313 AC: 4785 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.511 AC: 1773 AN: 3472

East Asian (EAS) AF: 0.0186 AC: 96 AN: 5170

South Asian (SAS) AF: 0.353 AC: 1704 AN: 4828

European-Finnish (FIN) AF: 0.433 AC: 4562 AN: 10544

Middle Eastern (MID) AF: 0.480 AC: 141 AN: 294

European-Non Finnish (NFE) AF: 0.453 AC: 30806 AN: 67964

Other (OTH) AF: 0.391 AC: 824 AN: 2108

Alfa AF: 0.399 Hom.: 1650

Bravo AF: 0.330

Asia WGS AF: 0.169 AC: 592 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.75
DANN	Benign	0.63
PhyloP100		-0.64
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: rs35780274; hg19: chr3-121993474;