chr3-122284035-G-GCATCCTGGTGAAAACCAACCGTGT
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PM4
The NM_000388.4(CASR):c.2083_2106dup(p.Ile695_Val702dup) variant causes a inframe insertion change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. C694C) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 32)
Consequence
CASR
NM_000388.4 inframe_insertion
NM_000388.4 inframe_insertion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 4.16
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 12 uncertain in NM_000388.4
PM2
Very rare variant in population databases, with high coverage;
PM4
Nonframeshift variant in NON repetitive region in NM_000388.4.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CASR | NM_000388.4 | c.2083_2106dup | p.Ile695_Val702dup | inframe_insertion | 7/7 | ENST00000639785.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CASR | ENST00000639785.2 | c.2083_2106dup | p.Ile695_Val702dup | inframe_insertion | 7/7 | 1 | NM_000388.4 | P1 | |
CASR | ENST00000498619.4 | c.2113_2136dup | p.Ile705_Val712dup | inframe_insertion | 7/7 | 1 | |||
CASR | ENST00000490131.7 | c.1852_1875dup | p.Ile618_Val625dup | inframe_insertion | 5/5 | 5 | |||
CASR | ENST00000638421.1 | c.2083_2106dup | p.Ile695_Val702dup | inframe_insertion | 7/7 | 5 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 33
GnomAD4 exome
Cov.:
33
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Autosomal dominant hypocalcemia 1;C1809471:Familial hypocalciuric hypercalcemia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 13, 2016 | This sequence change inserts 24 nucleotides in exon 7 of the CASR mRNA (c.2083_2106dup). This leads to the insertion of 8 amino acid residues in the CASR protein (p.Ile695_Val702dup) but otherwise preserves the integrity of the reading frame. 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. Experimental studies and protein prediction algorithms are not available for this variant, and the functional significance of the duplicated amino acids is currently unknown. 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. In summary, this variant is a novel duplication with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at