rs398124647

Variant names:

• chr2-47161851-T-A
• rs398124647
• NM_001743.6:c.293A>T

Your query was ambiguous. Multiple possible variants found:

• chr2-47161851-T-A
• chr2-47161851-T-C

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Moderate

The NM_001743.6(CALM2):​c.293A>T​(p.Asn98Ile) 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. N98S) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: CALM2 NM_001743.6 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 7.98
• Publications: 3 publications found

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

ENSG00000273269 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 11 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-C is described in ClinVar as Pathogenic. ClinVar VariationId is 96720.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, 0.919
• PP5: Variant 2-47161851-T-A is Pathogenic according to our data. 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CALM2	NM_001743.6	c.293A>T	p.Asn98Ile	missense_variant	Exon 5 of 6	ENST00000272298.12	NP_001734.1
CALM2	NM_001305624.1	c.437A>T	p.Asn146Ile	missense_variant	Exon 6 of 7		NP_001292553.1
CALM2	NM_001305625.2	c.185A>T	p.Asn62Ile	missense_variant	Exon 5 of 6		NP_001292554.1
CALM2	NM_001305626.1	c.185A>T	p.Asn62Ile	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	c.293A>T	p.Asn98Ile	missense_variant	Exon 5 of 6	1	NM_001743.6	ENSP00000272298.7
ENSG00000273269	ENST00000422269.1	n.101-8835A>T		intron_variant	Intron 2 of 8	2		ENSP00000476793.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

Long QT syndrome 1 Pathogenic:2

-

George Lab Vanderbilt University

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jul 06, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces asparagine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 98 of the CALM2 protein (p.Asn98Ile). 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: 24917665). In at least one individual the variant was observed to be de novo. This variant is also known as D97I. ClinVar contains an entry for this variant (Variation ID: 96721). 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: 24917665, 30348784). This variant disrupts the p.Asn98 amino acid residue in CALM2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24917665, 27100291, 27114410, 27165696, 28335032, 31283864). 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. -

Long QT syndrome 15 Pathogenic:1

Aug 01, 2014

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
CardioboostArm	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	28
DANN	Uncertain	0.98
DEOGEN2	Benign	0.36	.;T;.
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D;.;D
M_CAP	Pathogenic	0.66	D
MetaRNN	Pathogenic	0.92	D;D;D
MetaSVM	Uncertain	0.14	D
PhyloP100		8.0
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-8.0	D;D;D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	.;D;D
Sift4G	Uncertain	0.0020	D;D;D
Vest4		0.90
MutPred		0.71		Gain of catalytic residue at N98 (P = 0.0055);.;.;
MVP		0.81
MPC		2.6
ClinPred		1.0	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.88
gMVP		0.99
Mutation Taster		=0/100	disease causing (ClinVar)

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: rs398124647; hg19: chr2-47388990;