rs1555365887

Variant names:

• chr14-90401381-A-G
• rs1555365887
• NM_006888.6:c.157A>G

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM2 PP2

The NM_006888.6(CALM1):​c.157A>G​(p.Ile53Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CALM1 NM_006888.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.32
• Publications: 0 publications found

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]

CALM1 Gene-Disease associations (from GenCC):

• long QT syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• long QT syndrome 14

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P
• catecholaminergic polymorphic ventricular tachycardia 4

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• catecholaminergic polymorphic ventricular tachycardia

  Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: Orphanet, ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a chain Calmodulin-1 (size 147) in uniprot entity CALM1_HUMAN there are 18 pathogenic changes around while only 0 benign (100%) in NM_006888.6
• 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 catecholaminergic polymorphic ventricular tachycardia 4, catecholaminergic polymorphic ventricular tachycardia, long QT syndrome 14, long QT syndrome.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CALM1	NM_006888.6	c.157A>G	p.Ile53Val	missense_variant	Exon 3 of 6	ENST00000356978.9	NP_008819.1
CALM1	NM_001363670.2	c.160A>G	p.Ile54Val	missense_variant	Exon 3 of 6		NP_001350599.1
CALM1	NM_001363669.2	c.49A>G	p.Ile17Val	missense_variant	Exon 3 of 6		NP_001350598.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CALM1	ENST00000356978.9	c.157A>G	p.Ile53Val	missense_variant	Exon 3 of 6	1	NM_006888.6	ENSP00000349467.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Dec 03, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. 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 C25"). This variant has not been reported in the literature in individuals with a CALM1-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces isoleucine with valine at codon 53 of the CALM1 protein (p.Ile53Val). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and valine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
CardioboostArm	Benign	0.0014
BayesDel_addAF	Uncertain	0.012	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	25
DANN	Benign	0.93
Eigen	Benign	0.018
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	D;.;D;.;.;.
M_CAP	Pathogenic	0.40	D
MetaRNN	Uncertain	0.57	D;D;D;D;D;D
MetaSVM	Benign	-0.56	T
PhyloP100		9.3
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-0.81	N;N;N;.;N;N
REVEL	Uncertain	0.33
Sift4G	Benign	0.31	T;T;T;T;T;T
Polyphen		0.0050	.;.;B;.;.;.
Vest4		0.36, 0.40, 0.38, 0.38, 0.40
MutPred		0.61		.;.;Gain of disorder (P = 0.1589);.;.;.;
MVP		0.89
MPC		1.6
ClinPred		0.98	D
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.39
gMVP		0.80
Mutation Taster		=77/23	polymorphism

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

Other links and lift over

dbSNP: rs1555365887; hg19: chr14-90867725;