3-122282236-GGTAAGGGAAC-GTG

Position:

• chr3-122282236-GGTAAGGGAAC-GTG

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The NM_000388.4(CASR):​c.1732+1_1732+10delinsTG variant causes a splice donor, splice donor 5th base, intron 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CASR NM_000388.4 splice_donor, splice_donor_5th_base, intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.79

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.037998147 fraction of the gene. Cryptic splice site detected, with MaxEntScore 4, offset of 48, new splice context is: gggGTcagt. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CASR	NM_000388.4	c.1732+1_1732+10delinsTG		splice_donor_variant, splice_donor_5th_base_variant, intron_variant		ENST00000639785.2	NP_000379.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CASR	ENST00000639785.2	c.1732+1_1732+10delinsTG		splice_donor_variant, splice_donor_5th_base_variant, intron_variant		1	NM_000388.4	ENSP00000491584	P1
CASR	ENST00000498619.4	c.1762+1_1762+10delinsTG		splice_donor_variant, splice_donor_5th_base_variant, intron_variant		1		ENSP00000420194
CASR	ENST00000490131.7	c.1501+1_1501+10delinsTG		splice_donor_variant, splice_donor_5th_base_variant, intron_variant		5		ENSP00000418685
CASR	ENST00000638421.1	c.1732+1_1732+10delinsTG		splice_donor_variant, splice_donor_5th_base_variant, intron_variant		5		ENSP00000492190	P1

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal dominant hypocalcemia 1;C1809471:Familial hypocalciuric hypercalcemia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 26, 2016

This sequence change affects a donor splice site in intron 6 of the CASR gene. It is expected to disrupt RNA splicing and likely results in a disrupted protein product. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a CASR-related disease. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. Also, this donor splice site variant lies in the last intron of the gene, and its impact on protein function is uncertain. In summary, donor splice site variants are typically truncating (PMID: 16199547); however, this particular donor splice site variant lies in the last intron of the gene with uncertain impact on protein function. Without additional functional and/or genetic data, this variant has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1064792970; hg19: chr3-122001084;