rs1553431791
Positions:
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong
The NM_001743.6(CALM2):c.179-8C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: not found (cov: 31)
Consequence
CALM2
NM_001743.6 splice_region, intron
NM_001743.6 splice_region, intron
Scores
2
Splicing: ADA: 0.0003732
2
Clinical Significance
Conservation
PhyloP100: -0.699
Genes affected
CALM2 (HGNC:1445): (calmodulin 2) This gene is a member of the calmodulin gene family. There are three distinct calmodulin genes dispersed throughout the genome that encode the identical protein, but differ at the nucleotide level. Calmodulin is a calcium binding protein that plays a role in signaling pathways, cell cycle progression and proliferation. Several infants with severe forms of long-QT syndrome (LQTS) who displayed life-threatening ventricular arrhythmias together with delayed neurodevelopment and epilepsy were found to have mutations in either this gene or another member of the calmodulin gene family (PMID:23388215). Mutations in this gene have also been identified in patients with less severe forms of LQTS (PMID:24917665), while mutations in another calmodulin gene family member have been associated with catecholaminergic polymorphic ventricular tachycardia (CPVT)(PMID:23040497), a rare disorder thought to be the cause of a significant fraction of sudden cardiac deaths in young individuals. Pseudogenes of this gene are found on chromosomes 10, 13, and 17. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Mar 2015]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.84).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CALM2 | NM_001743.6 | c.179-8C>G | splice_region_variant, intron_variant | ENST00000272298.12 | NP_001734.1 | |||
CALM2 | NM_001305624.1 | c.323-8C>G | splice_region_variant, intron_variant | NP_001292553.1 | ||||
CALM2 | NM_001305625.2 | c.71-8C>G | splice_region_variant, intron_variant | NP_001292554.1 | ||||
CALM2 | NM_001305626.1 | c.71-8C>G | splice_region_variant, intron_variant | NP_001292555.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CALM2 | ENST00000272298.12 | c.179-8C>G | splice_region_variant, intron_variant | 1 | NM_001743.6 | ENSP00000272298.7 | ||||
ENSG00000273269 | ENST00000422269.1 | n.100+8334C>G | intron_variant | 2 | ENSP00000476793.1 |
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD3 genomes
Cov.:
31
GnomAD4 exome Cov.: 29
GnomAD4 exome
Cov.:
29
GnomAD4 genome Cov.: 31
GnomAD4 genome
Cov.:
31
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Long QT syndrome 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Aug 07, 2018 | This variant has not been reported in the literature in individuals with CALM2-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change falls in intron 3 of the CALM2 gene. It does not directly change the encoded amino acid sequence of the CALM2 protein. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
not provided Uncertain:1
Uncertain significance, no assertion criteria provided | provider interpretation | Stanford Center for Inherited Cardiovascular Disease, Stanford University | Aug 15, 2017 | CALM2, Intron 3, c.179-8C>G (Intronic), heterozygous, Uncertain Significance Given the lack of case data, we consider this variant a variant of uncertain significance and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). CALM2 variants have been implicated in a long QT/CPVT-like phenotype (Boczek et al 2016). To date the reported cases have been quite severe with early childhood onset. Given the way some of these cases were ascertained (from large unexplained LQTS cohorts) it is unlikely that this greater severity is attributable primarily to ascertainment bias. Per the lab report this variant has not been reported in association with disease. Per the lab report "Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variantdisrupt the consensus splice site, but this prediction has not been confirmed by published studies." There is no variation at this nucleotide listed in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Latino, and Ashkenazi descent. The average coverage at that site in gnomAD is >30x. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at