3-122228678-T-G

Variant names:

• chr3-122228678-T-G
• rs4678172
• NM_000388.4:c.-242-25270T>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000388.4(CASR):​c.-242-25270T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.718 in 152,100 control chromosomes in the GnomAD database, including 39,471 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 (39471 hom., cov: 32)
• Consequence: CASR NM_000388.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0580
• Publications: 3 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=-0.95).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.808 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASR	NM_000388.4	MANE Select	c.-242-25270T>G		intron	N/A	NP_000379.3
	CASR	NM_001178065.2		c.-242-25270T>G		intron	N/A	NP_001171536.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASR	ENST00000639785.2	TSL:1 MANE Select	c.-242-25270T>G		intron	N/A	ENSP00000491584.2
	CASR	ENST00000498619.4	TSL:1	c.-242-25270T>G		intron	N/A	ENSP00000420194.1
	CASR	ENST00000638421.1	TSL:5	c.-242-25270T>G		intron	N/A	ENSP00000492190.1

Frequencies

GnomAD3 genomes AF: 0.718 AC: 109107 AN: 151982 Hom.: 39452 Cov.: 32

Gnomad AFR AF: 0.668

Gnomad AMI AF: 0.838

Gnomad AMR AF: 0.819

Gnomad ASJ AF: 0.762

Gnomad EAS AF: 0.466

Gnomad SAS AF: 0.643

Gnomad FIN AF: 0.694

Gnomad MID AF: 0.756

Gnomad NFE AF: 0.749

Gnomad OTH AF: 0.734

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

GnomAD4 genome AF: 0.718 AC: 109177 AN: 152100 Hom.: 39471 Cov.: 32 AF XY: 0.718 AC XY: 53413 AN XY: 74340

African (AFR) AF: 0.668 AC: 27704 AN: 41482

American (AMR) AF: 0.820 AC: 12532 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.762 AC: 2644 AN: 3472

East Asian (EAS) AF: 0.467 AC: 2420 AN: 5182

South Asian (SAS) AF: 0.643 AC: 3100 AN: 4822

European-Finnish (FIN) AF: 0.694 AC: 7331 AN: 10560

Middle Eastern (MID) AF: 0.762 AC: 224 AN: 294

European-Non Finnish (NFE) AF: 0.749 AC: 50923 AN: 67976

Other (OTH) AF: 0.727 AC: 1535 AN: 2112

Alfa AF: 0.725 Hom.: 6052

Bravo AF: 0.726

Asia WGS AF: 0.539 AC: 1878 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	2.3
DANN	Benign	0.40
PhyloP100		0.058
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: rs4678172; hg19: chr3-121947525;