2-47161851-T-C

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1PM2PM5PP2PP3_ModeratePP5_Very_Strong

The NM_001743.6(CALM2):c.293A>G(p.Asn98Ser) 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N98I) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 31)

Consequence

CALM2
NM_001743.6 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 7.98

Publications

3 publications found

Variant links:

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]

CALM2 Gene-Disease associations (from GenCC):

long QT syndrome
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
long QT syndrome 15
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
catecholaminergic polymorphic ventricular tachycardia
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Genomics England PanelApp, ClinGen, G2P

CALM2 links:

ENSG00000273269 (HGNC:):

ENSG00000273269 links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 17 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_001743.6

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr2-47161851-T-A is described in ClinVar as Pathogenic. ClinVar VariationId is 96721.Status of the report is criteria_provided_single_submitter, 1 stars.

PP2

Missense variant in the CALM2 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 18 curated pathogenic missense variants (we use a threshold of 10). The gene has 5 curated benign missense variants. Gene score misZ: 2.7928 (below the threshold of 3.09). Trascript score misZ: 3.5506 (above the threshold of 3.09). GenCC associations: The gene is linked to catecholaminergic polymorphic ventricular tachycardia, long QT syndrome 15, long QT syndrome.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.862

PP5

Variant 2-47161851-T-C is Pathogenic according to our data. Variant chr2-47161851-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 96720.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
CALM2	NM_001743.6 link	c.293A>G	p.Asn98Ser	missense_variant	Exon 5 of 6	ENST00000272298.12	NP_001734.1
CALM2	NM_001305624.1 link	c.437A>G	p.Asn146Ser	missense_variant	Exon 6 of 7		NP_001292553.1
CALM2	NM_001305625.2 link	c.185A>G	p.Asn62Ser	missense_variant	Exon 5 of 6		NP_001292554.1
CALM2	NM_001305626.1 link	c.185A>G	p.Asn62Ser	missense_variant	Exon 4 of 5		NP_001292555.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CALM2	ENST00000272298.12 link	c.293A>G	p.Asn98Ser	missense_variant	Exon 5 of 6	1	NM_001743.6	ENSP00000272298.7
ENSG00000273269	ENST00000422269.1 link	n.101-8835A>G		intron_variant	Intron 2 of 8	2		ENSP00000476793.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Long QT syndrome 1

Pathogenic:2

Jul 19, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces asparagine with serine at codon 98 of the CALM2 protein (p.Asn98Ser). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and serine. For these reasons, this variant has been classified as Pathogenic. This variant has been reported to affect CALM2 protein function (PMID: 28335032, 27165696). This variant has been observed in individual(s) with long QT syndrome or catecholaminergic polymorphic ventricular tachycardia (PMID: 27100291, 24917665, 27114410, 31283864). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 96720). This variant is not present in population databases (ExAC no frequency). -

George Lab Vanderbilt University

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Long QT syndrome 15

Pathogenic:1

Aug 01, 2014

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Long QT syndrome

Pathogenic:1

Jan 08, 2024

Dept of Medical Biology, Uskudar University

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

Criteria: PS3_Moderate PS2_Strong, PM1, PM2, PP3 -

Cardiovascular phenotype

Pathogenic:1

May 27, 2025

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.N98S pathogenic mutation (also known as c.293A>G), located in coding exon 5 of the CALM2 gene, results from an A to G substitution at nucleotide position 293. The asparagine at codon 98 is replaced by serine, an amino acid with highly similar properties. This missense alteration is located in a region that has a low rate of benign missense variation (Lek M et al. Nature. 2016 Aug 18;536(7616):285-91; DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources. Firth H.V. et al. 2009. Am.J.Hum.Genet. 84, 524-533 (DOI: dx.doi.org/10/1016/j.ajhg.2009.03.010)). This variant was reported in individual(s) with features consistent with calmodulinopathy; in at least one individual, it was determined to be de novo (Makita N et al. Circ Cardiovasc Genet, 2014 Aug;7:466-74; Jiménez-Jáimez J et al. PLoS One, 2016 Apr;11:e0153851; Crotti L et al. Eur Heart J, 2019 Sep;40:2964-2975; Fujita S et al. Pediatr Int, 2019 Sep;61:852-858; Fukuyama M et al. Circ J, 2023 Nov;87:1828-1835). An animal model expressing this variant exhibited phenotype(s) consistent with CALM2-related disease (Tsai WC et al. Circulation, 2020 Nov;142:1937-1955). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this variant is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

CardioboostArm

Pathogenic

1.0

BayesDel_addAF

Benign

-0.011

BayesDel_noAF

Benign

-0.25

CADD

Uncertain

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.30

.;T;.

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

D;.;D

M_CAP

Pathogenic

0.61

MetaRNN

Pathogenic

0.86

D;D;D

MetaSVM

Uncertain

0.034

PhyloP100

8.0

PrimateAI

Pathogenic

0.90

PROVEAN

Uncertain

-4.4

D;D;D

REVEL

Pathogenic

0.83

Sift

Uncertain

0.0010

.;D;D

Sift4G

Benign

0.18

T;T;T

Vest4

0.83

MVP

0.88

MPC

1.5

ClinPred

0.97

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.70

gMVP

0.90

Mutation Taster

=21/79

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over