rs1553431711

Variant names:

• chr2-47161816-T-A
• rs1553431711
• NM_001743.6:c.328A>T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PP2 PP3_Moderate PP5

The NM_001743.6(CALM2):​c.328A>T​(p.Met110Leu) 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 Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 31)
• Consequence: CALM2 NM_001743.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 7.98
• Publications: 0 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: Likely_pathogenic. The variant received 8 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_001743.6
• PM2: Very rare variant in population databases, with high coverage
• 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, 0.867
• PP5: Variant 2-47161816-T-A is Pathogenic according to our data. Variant chr2-47161816-T-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 458191.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CALM2	NM_001743.6	c.328A>T	p.Met110Leu	missense_variant	Exon 5 of 6	ENST00000272298.12	NP_001734.1
CALM2	NM_001305624.1	c.472A>T	p.Met158Leu	missense_variant	Exon 6 of 7		NP_001292553.1
CALM2	NM_001305625.2	c.220A>T	p.Met74Leu	missense_variant	Exon 5 of 6		NP_001292554.1
CALM2	NM_001305626.1	c.220A>T	p.Met74Leu	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.328A>T	p.Met110Leu	missense_variant	Exon 5 of 6	1	NM_001743.6	ENSP00000272298.7
ENSG00000273269	ENST00000422269.1	n.101-8800A>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: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Long QT syndrome 1 Pathogenic:1

Apr 02, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 tolerated, but these predictions have not been confirmed by published functional studies. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a CALM2-related disease. This sequence change replaces methionine with leucine at codon 110 of the CALM2 protein (p.Met110Leu). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and leucine. In summary, this variant is a novel missense change that arose de novo in an affected individual. This evidence indicates that the variant is pathogenic, but additional data is needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant has been shown to arise de novo in an individual affected with a CALM2-related condition (Invitae). -

Inborn genetic diseases Uncertain:1

May 11, 2015

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
CardioboostArm	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Uncertain	25
DANN	Benign	0.95
DEOGEN2	Benign	0.30	.;T;.
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;.;D
M_CAP	Pathogenic	0.48	D
MetaRNN	Pathogenic	0.87	D;D;D
MetaSVM	Uncertain	0.14	D
PhyloP100		8.0
PrimateAI	Pathogenic	0.95	D
PROVEAN	Benign	-2.3	N;N;N
REVEL	Uncertain	0.58
Sift	Pathogenic	0.0	.;D;D
Sift4G	Benign	0.44	T;T;T
Vest4		0.59
MutPred		0.72		Loss of loop (P = 0.1242);.;.;
MVP		0.94
MPC		2.0
ClinPred		0.91	D
GERP RS		5.7
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6
Varity_R		0.86
gMVP		0.96
Mutation Taster		=31/69	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: rs1553431711; hg19: chr2-47388955;