rs730882253
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP2PP3_ModeratePP5_Moderate
The NM_006888.6(CALM1):c.268T>C(p.Phe90Leu) variant causes a missense change involving the alteration of a conserved nucleotide. 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: 33)
Consequence
CALM1
NM_006888.6 missense
NM_006888.6 missense
Scores
8
7
1
Clinical Significance
Conservation
PhyloP100: 7.97
Genes affected
CALM1 (HGNC:1442): (calmodulin 1) This gene encodes one of three calmodulin proteins which are members of the EF-hand calcium-binding protein family. Calcium-induced activation of calmodulin regulates and modulates the function of cardiac ion channels. Two pseudogenes have been identified on chromosome 7 and X. Multiple transcript variants encoding different isoforms have been found for this gene.A missense mutation in the CALM1 gene has been associated with ventricular tachycardia.[provided by RefSeq, May 2020]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
PM1
?
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_006888.6
PM2
?
Very rare variant in population databases, with high coverage;
PP2
?
Missense variant where missense usually causes diseases, CALM1
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.928
PP5
?
Variant 14-90403951-T-C is Pathogenic according to our data. Variant chr14-90403951-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 183232.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CALM1 | NM_006888.6 | c.268T>C | p.Phe90Leu | missense_variant | 4/6 | ENST00000356978.9 | |
CALM1 | NM_001363670.2 | c.271T>C | p.Phe91Leu | missense_variant | 4/6 | ||
CALM1 | NM_001363669.2 | c.160T>C | p.Phe54Leu | missense_variant | 4/6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CALM1 | ENST00000356978.9 | c.268T>C | p.Phe90Leu | missense_variant | 4/6 | 1 | NM_006888.6 | P1 | |
ENST00000555853.1 | n.45-1173A>G | intron_variant, non_coding_transcript_variant | 3 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome Cov.: 27
GnomAD4 exome
Cov.:
27
GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Long QT syndrome 14 Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 28, 2014 | - - |
Likely pathogenic, criteria provided, single submitter | curation | SIB Swiss Institute of Bioinformatics | Jul 22, 2020 | This variant is interpreted as likely pathogenic for Long QT syndrome 14, autosomal dominant. The following ACMG Tag(s) were applied: Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium (PM2); Multiple lines of computational evidence support a deleterious effect on the gene or gene product (PP3); Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (PP1) (PMID:24076290); Well-established functional studies show a deleterious effect (PS3 downgraded to moderate) (PMID:27165696; 25036739). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
CardioboostArm
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;.;D;.;.
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D
MetaSVM
Uncertain
D
MutationTaster
Benign
D;D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;D;D;D;D
REVEL
Pathogenic
Sift4G
Uncertain
D;D;T;D;D
Polyphen
0.96
.;.;P;.;.
Vest4
0.95, 0.96, 0.95, 0.95
MutPred
0.74
.;.;Loss of methylation at K96 (P = 0.0988);.;.;
MVP
MPC
2.5
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