rs77653008
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Variant summary
Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_ModerateBP6_Very_StrongBP7BS2
The NM_001743.6(CALM2):c.240A>T(p.Thr80=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000743 in 1,612,768 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).
Frequency
Genomes: 𝑓 0.0043 ( 4 hom., cov: 31)
Exomes 𝑓: 0.00037 ( 4 hom. )
Consequence
CALM2
NM_001743.6 synonymous
NM_001743.6 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 2.27
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 Benign. Variant got -15 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.43).
BP6
?
Variant 2-47162331-T-A is Benign according to our data. Variant chr2-47162331-T-A is described in ClinVar as [Benign]. Clinvar id is 239038.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47162331-T-A is described in Lovd as [Benign].
BP7
?
Synonymous conserved (PhyloP=2.27 with no splicing effect.
BS2
?
High AC in GnomAd4 at 654 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CALM2 | NM_001743.6 | c.240A>T | p.Thr80= | synonymous_variant | 4/6 | ENST00000272298.12 | |
CALM2 | NM_001305624.1 | c.384A>T | p.Thr128= | synonymous_variant | 5/7 | ||
CALM2 | NM_001305625.2 | c.132A>T | p.Thr44= | synonymous_variant | 4/6 | ||
CALM2 | NM_001305626.1 | c.132A>T | p.Thr44= | synonymous_variant | 3/5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CALM2 | ENST00000272298.12 | c.240A>T | p.Thr80= | synonymous_variant | 4/6 | 1 | NM_001743.6 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00428 AC: 652AN: 152222Hom.: 4 Cov.: 31
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GnomAD3 exomes AF: 0.00109 AC: 272AN: 250454Hom.: 3 AF XY: 0.000768 AC XY: 104AN XY: 135362
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GnomAD4 exome AF: 0.000373 AC: 545AN: 1460428Hom.: 4 Cov.: 30 AF XY: 0.000306 AC XY: 222AN XY: 726538
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GnomAD4 genome ? AF: 0.00429 AC: 654AN: 152340Hom.: 4 Cov.: 31 AF XY: 0.00428 AC XY: 319AN XY: 74500
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ClinVar
Significance: Benign
Submissions summary: Benign:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:1
Benign, criteria provided, single submitter | clinical testing | GeneDx | Jul 19, 2017 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Long QT syndrome 1 Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | - - |
Cardiovascular phenotype Benign:1
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 16, 2019 | This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at