chr3-122254190-A-G
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1PS1_ModeratePM2PP5_Moderate
The NM_000388.4(CASR):c.1A>G(p.Met1?) variant causes a start lost change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).
Frequency
Genomes: not found (cov: 32)
Consequence
CASR
NM_000388.4 start_lost
NM_000388.4 start_lost
Scores
3
4
4
Clinical Significance
Conservation
PhyloP100: 6.28
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 Pathogenic. Variant got 14 ACMG points.
PVS1
?
Start lost variant, no new inframe start found.
PS1
?
Another start lost variant in NM_000388.4 (CASR) was described as [Likely_pathogenic] in ClinVar as 2035301
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 3-122254190-A-G is Pathogenic according to our data. Variant chr3-122254190-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1321411.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CASR | NM_000388.4 | c.1A>G | p.Met1? | start_lost | 2/7 | ENST00000639785.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CASR | ENST00000639785.2 | c.1A>G | p.Met1? | start_lost | 2/7 | 1 | NM_000388.4 | P1 | |
CASR | ENST00000498619.4 | c.1A>G | p.Met1? | start_lost | 2/7 | 1 | |||
CASR | ENST00000638421.1 | c.1A>G | p.Met1? | start_lost | 2/7 | 5 | P1 | ||
CASR | ENST00000490131.7 | c.1A>G | p.Met1? | start_lost | 1/5 | 5 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Familial hypocalciuric hypercalcemia Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 23, 2021 | Variant summary: CASR c.1A>G (p.Met1?) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. The mutation is predicted to disrupt the original Kozak sequence (AXXATGG), altering the protein start site. Computational analysis using a program that predicts start sites identified five potential Kozak sequences: three upstream and one downstream of the original ATG site, which change the protein reading frame and create short sequences with a stop codon, and another downstream in-frame start codon in exon 3 (Met74) 222 bp downstream (Andrade_2006). The variant was absent in 251304 control chromosomes. To our knowledge, no occurrence of c.1A>G in individuals affected with Familial Hypocalciuric Hypercalcemia and no experimental evidence demonstrating its impact on protein function have been reported. However, a different nucleotide alteration c.2T>G, resulting in the same translational impact, namely p.Met1? has been reported in individuals from at-least one family affected with familial hypocalciuric hypercalcaemia and neonatal severe hyperparathyroidism (example, Andrade_2006). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
Cadd
Benign
Dann
Uncertain
DEOGEN2
Benign
T;T;.;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Uncertain
D
MutationTaster
Benign
D;D;D
Polyphen
B;B;.;.
Vest4
0.67, 0.69
MutPred
Loss of glycosylation at S5 (P = 0.0332);Loss of glycosylation at S5 (P = 0.0332);Loss of glycosylation at S5 (P = 0.0332);Loss of glycosylation at S5 (P = 0.0332);
MVP
0.94
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
No publications associated with this variant yet.