3-122191781-T-A

Variant names:

• chr3-122191781-T-A
• rs1501900
• NM_000388.4:c.-243+7969T>A

Variant summary

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

The NM_000388.4(CASR):​c.-243+7969T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.821 in 152,248 control chromosomes in the GnomAD database, including 52,161 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 0.82 (52161 hom., cov: 34)
• Consequence: CASR NM_000388.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.58
• Publications: 7 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=-1.0).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.902 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.-243+7969T>A		intron	N/A	NP_000379.3
	CASR	NM_001178065.2		c.-243+7252T>A		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.-243+7969T>A		intron	N/A	ENSP00000491584.2
	CASR	ENST00000498619.4	TSL:1	c.-243+7252T>A		intron	N/A	ENSP00000420194.1
	CASR	ENST00000638421.1	TSL:5	c.-243+7252T>A		intron	N/A	ENSP00000492190.1

Frequencies

GnomAD3 genomes AF: 0.821 AC: 124945 AN: 152130 Hom.: 52115 Cov.: 34

Gnomad AFR AF: 0.910

Gnomad AMI AF: 0.841

Gnomad AMR AF: 0.864

Gnomad ASJ AF: 0.801

Gnomad EAS AF: 0.403

Gnomad SAS AF: 0.621

Gnomad FIN AF: 0.770

Gnomad MID AF: 0.832

Gnomad NFE AF: 0.812

Gnomad OTH AF: 0.826

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

GnomAD4 genome AF: 0.821 AC: 125045 AN: 152248 Hom.: 52161 Cov.: 34 AF XY: 0.815 AC XY: 60661 AN XY: 74440

African (AFR) AF: 0.910 AC: 37820 AN: 41560

American (AMR) AF: 0.865 AC: 13232 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.801 AC: 2778 AN: 3470

East Asian (EAS) AF: 0.404 AC: 2088 AN: 5170

South Asian (SAS) AF: 0.621 AC: 2996 AN: 4824

European-Finnish (FIN) AF: 0.770 AC: 8152 AN: 10582

Middle Eastern (MID) AF: 0.833 AC: 245 AN: 294

European-Non Finnish (NFE) AF: 0.812 AC: 55238 AN: 68020

Other (OTH) AF: 0.818 AC: 1729 AN: 2114

Alfa AF: 0.819 Hom.: 6382

Bravo AF: 0.836

Asia WGS AF: 0.495 AC: 1724 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.26
DANN	Benign	0.41
PhyloP100		-1.6
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: rs1501900; hg19: chr3-121910628;