rs1553768972

Variant names:

• chr3-122283923-TC-T
• rs1553768972
• NM_000388.4:c.1972delC

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PS3 PM2 PP5_Moderate

The NM_000388.4(CASR):​c.1972delC​(p.Leu658CysfsTer40) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). ClinVar reports functional evidence for this variant: "SCV000638035: Experimental data has shown that similar truncated proteins lacking the last two or four transmembrane domains are not properly glycosylated, do not localize to the cell surface, and have an impaired response to extracellular calcium (PMID:9395465).". Synonymous variant affecting the same amino acid position (i.e. L658L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CASR NM_000388.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.91
• Publications: 0 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: Pathogenic. The variant received 16 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 96 pathogenic variants in the truncated region.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000638035: Experimental data has shown that similar truncated proteins lacking the last two or four transmembrane domains are not properly glycosylated, do not localize to the cell surface, and have an impaired response to extracellular calcium (PMID: 9395465).
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-122283923-TC-T is Pathogenic according to our data. Variant chr3-122283923-TC-T is described in ClinVar as Pathogenic. ClinVar VariationId is 463917.Status of the report is criteria_provided_single_submitter, 1 stars.

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.1972delC	p.Leu658CysfsTer40	frameshift	Exon 7 of 7	NP_000379.3
	CASR	NM_001178065.2		c.2002delC	p.Leu668CysfsTer40	frameshift	Exon 7 of 7	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.1972delC	p.Leu658CysfsTer40	frameshift	Exon 7 of 7	ENSP00000491584.2	P41180-1
	CASR	ENST00000498619.4	TSL:1	c.2002delC	p.Leu668CysfsTer40	frameshift	Exon 7 of 7	ENSP00000420194.1	P41180-2
	CASR	ENST00000638421.1	TSL:5	c.1972delC	p.Leu658CysfsTer40	frameshift	Exon 7 of 7	ENSP00000492190.1	P41180-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Familial hypocalciuric hypercalcemia;C3715128:Autosomal dominant hypocalcemia 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.9
Mutation Taster		=0/200	disease causing (ClinVar)

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: rs1553768972; hg19: chr3-122002770;