rs730882254

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.287A>T(p.Asp96Val) variant causes a missense, splice region 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. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D96Y) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 31)

Consequence

CALM2
NM_001743.6 missense, splice_region

Scores

Splicing: ADA: 0.7621

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 7.98

Publications

4 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 3 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 chr2-47161858-C-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 641544.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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, 0.927

PP5

Variant 2-47161857-T-A is Pathogenic according to our data. Variant chr2-47161857-T-A is described in ClinVar as Pathogenic. ClinVar VariationId is 183233.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.287A>T	p.Asp96Val	missense_variant, splice_region_variant	Exon 5 of 6	ENST00000272298.12	NP_001734.1
CALM2	NM_001305624.1 link	c.431A>T	p.Asp144Val	missense_variant, splice_region_variant	Exon 6 of 7		NP_001292553.1
CALM2	NM_001305625.2 link	c.179A>T	p.Asp60Val	missense_variant, splice_region_variant	Exon 5 of 6		NP_001292554.1
CALM2	NM_001305626.1 link	c.179A>T	p.Asp60Val	missense_variant, splice_region_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.287A>T	p.Asp96Val	missense_variant, splice_region_variant	Exon 5 of 6	1	NM_001743.6	ENSP00000272298.7
ENSG00000273269	ENST00000422269.1 link	n.101-8841A>T		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:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Long QT syndrome 1

Pathogenic:1

Nov 26, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with long QT syndrome (PMID: 23388215). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 183233). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects CALM2 function (PMID: 23388215). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This variant disrupts the p.Asp96 amino acid residue in CALM2. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 96 of the CALM2 protein (p.Asp96Val). -

Long QT syndrome 15

Pathogenic:1

Mar 05, 2013

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

not provided

Pathogenic:1

Apr 07, 2021

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate a damaging effect as this variant results in decreased calcium affinity in the C-domain of the protein (Crotti et al., 2013; Sondergaard et al., 2015); This variant is associated with the following publications: (PMID: 30348784, 24563457, 27927985, 27516456, 27815504, 26164367, 24958779, 24816216, 26969752, 23388215, 26309258, 29932249) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

CardioboostArm

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.24

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.52

.;D;.

Eigen

Pathogenic

1.2

Eigen_PC

Pathogenic

1.0

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.76

T;.;T

M_CAP

Pathogenic

0.57

MetaRNN

Pathogenic

0.93

D;D;D

MetaSVM

Benign

-0.40

PhyloP100

8.0

PrimateAI

Pathogenic

0.94

PROVEAN

Pathogenic

-8.1

D;D;D

REVEL

Pathogenic

0.77

Sift

Pathogenic

0.0

.;D;D

Sift4G

Uncertain

0.0040

D;D;D

Vest4

0.97

MVP

0.93

MPC

2.9

ClinPred

1.0

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.82

gMVP

0.99

Mutation Taster

=1/99

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.76

dbscSNV1_RF

Benign

0.58

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

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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