3-122258435-G-T

Variant names:

• chr3-122258435-G-T
• rs10934578
• NM_000388.4:c.492+1048G>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+1048G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.31 in 139,012 control chromosomes in the GnomAD database, including 7,364 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 0.31 (7364 hom., cov: 26)
• Consequence: CASR NM_000388.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0640
• Publications: 22 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, Labcorp Genetics (formerly Invitae), ClinGen
• familial hypocalciuric hypercalcemia 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Illumina, Orphanet, ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• neonatal severe primary hyperparathyroidism

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, 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=-0.78).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.539 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000388.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASR	NM_000388.4	MANE Select	c.492+1048G>T		intron	N/A	NP_000379.3
	CASR	NM_001178065.2		c.492+1048G>T		intron	N/A	NP_001171536.2	P41180-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASR	ENST00000639785.2	TSL:1 MANE Select	c.492+1048G>T		intron	N/A	ENSP00000491584.2	P41180-1
	CASR	ENST00000498619.4	TSL:1	c.492+1048G>T		intron	N/A	ENSP00000420194.1	P41180-2
	CASR	ENST00000638421.1	TSL:5	c.492+1048G>T		intron	N/A	ENSP00000492190.1	P41180-1

Frequencies

GnomAD3 genomes AF: 0.310 AC: 43088 AN: 138928 Hom.: 7355 Cov.: 26

Gnomad AFR AF: 0.133

Gnomad AMI AF: 0.167

Gnomad AMR AF: 0.415

Gnomad ASJ AF: 0.512

Gnomad EAS AF: 0.556

Gnomad SAS AF: 0.512

Gnomad FIN AF: 0.362

Gnomad MID AF: 0.519

Gnomad NFE AF: 0.334

Gnomad OTH AF: 0.363

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

GnomAD4 genome AF: 0.310 AC: 43119 AN: 139012 Hom.: 7364 Cov.: 26 AF XY: 0.318 AC XY: 21309 AN XY: 66948

African (AFR) AF: 0.133 AC: 4752 AN: 35644

American (AMR) AF: 0.415 AC: 5652 AN: 13610

Ashkenazi Jewish (ASJ) AF: 0.512 AC: 1764 AN: 3444

East Asian (EAS) AF: 0.557 AC: 2776 AN: 4988

South Asian (SAS) AF: 0.514 AC: 2288 AN: 4448

European-Finnish (FIN) AF: 0.362 AC: 2952 AN: 8154

Middle Eastern (MID) AF: 0.516 AC: 131 AN: 254

European-Non Finnish (NFE) AF: 0.334 AC: 21964 AN: 65688

Other (OTH) AF: 0.365 AC: 692 AN: 1894

Alfa AF: 0.322 Hom.: 14155

Bravo AF: 0.287

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	6.6
DANN	Benign	0.53
PhyloP100		0.064
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: rs10934578; hg19: chr3-121977282; COSMIC: COSV56141790; COSMIC: COSV56141790;