rs1555366045

Variant names:

• chr14-90404491-G-A
• rs1555366045
• NM_006888.6:c.398G>A

Your query was ambiguous. Multiple possible variants found:

• chr14-90404491-G-A
• chr14-90404491-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP2 PP3_Moderate PP5_Moderate

The NM_006888.6(CALM1):​c.398G>A​(p.Gly133Glu) 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
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.94

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]

ENSG00000258424 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the CALM1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 16 curated pathogenic missense variants (we use a threshold of 10). The gene has 5 curated benign missense variants. Gene score misZ: 3.051 (below the threshold of 3.09). Trascript score misZ: 3.5833 (above the threshold of 3.09). GenCC associations: The gene is linked to long QT syndrome, catecholaminergic polymorphic ventricular tachycardia 4, long QT syndrome 14, catecholaminergic polymorphic ventricular tachycardia.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.861
• PP5: Variant 14-90404491-G-A is Pathogenic according to our data. Variant chr14-90404491-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 542137.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CALM1	NM_006888.6	c.398G>A	p.Gly133Glu	missense_variant	Exon 5 of 6	ENST00000356978.9	NP_008819.1
CALM1	NM_001363670.2	c.401G>A	p.Gly134Glu	missense_variant	Exon 5 of 6		NP_001350599.1
CALM1	NM_001363669.2	c.290G>A	p.Gly97Glu	missense_variant	Exon 5 of 6		NP_001350598.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CALM1	ENST00000356978.9	c.398G>A	p.Gly133Glu	missense_variant	Exon 5 of 6	1	NM_006888.6	ENSP00000349467.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Catecholaminergic polymorphic ventricular tachycardia 4;C4015671:Long QT syndrome 14 Pathogenic:1

Jun 04, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (ExAC no frequency). This variant has been observed to be de novo in an individual affected with a CALM1-related disease (Invitae). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C65"). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This sequence change replaces glycine with glutamic acid at codon 133 of the CALM1 protein (p.Gly133Glu). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and glutamic acid. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Pathogenic	28
DANN	Uncertain	0.99
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D;.;D;.;.;.
M_CAP	Pathogenic	0.39	D
MetaRNN	Pathogenic	0.86	D;D;D;D;D;D
MetaSVM	Uncertain	0.15	D
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-5.0	D;D;D;.;D;D
REVEL	Uncertain	0.62
Sift4G	Uncertain	0.015	D;D;D;D;D;D
Polyphen		0.89	.;.;P;.;.;.
Vest4		0.81, 0.84, 0.88, 0.82
MutPred		0.68		.;.;Gain of solvent accessibility (P = 0.024);.;.;.;
MVP		0.91
MPC		2.6
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.85
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1555366045; hg19: chr14-90870835;