rs398124648

chr2-47161748-A-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP2 PP3 PP5_Moderate

The NM_001743.6(CALM2):c.396T>G(p.Asp132Glu) variant causes a missense change involving the alteration of a non-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. D132G) 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: 1.74

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]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 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 chr2-47161749-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 955533.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant where missense usually causes diseases, CALM2
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.787
• PP5: Variant 2-47161748-A-C is Pathogenic according to our data. Variant chr2-47161748-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 96722.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CALM2	NM_001743.6	c.396T>G	p.Asp132Glu	missense_variant	5/6	ENST00000272298.12
CALM2	NM_001305624.1	c.540T>G	p.Asp180Glu	missense_variant	6/7
CALM2	NM_001305625.2	c.288T>G	p.Asp96Glu	missense_variant	5/6
CALM2	NM_001305626.1	c.288T>G	p.Asp96Glu	missense_variant	4/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CALM2	ENST00000272298.12	c.396T>G	p.Asp132Glu	missense_variant	5/6	1	NM_001743.6	P1

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 15 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Aug 20, 2018	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 2014	- -

Long QT syndrome 1 Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

George Lab Vanderbilt University

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- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
CardioboostArm	Uncertain	0.38
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
Cadd	Uncertain	23
Dann	Benign	0.89
Eigen	Benign	0.15
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.94	D;D;.;D
M_CAP	Pathogenic	0.50	D
MetaRNN	Pathogenic	0.79	D;D;D;D
MetaSVM	Uncertain	-0.21	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-2.4	N;.;D;D
REVEL	Pathogenic	0.77
Sift4G	Uncertain	0.033	D;D;D;D
Vest4		0.78
MutPred		0.77		Gain of disorder (P = 0.13);.;.;.;
MVP		0.91
MPC		2.2
ClinPred		0.63	D
GERP RS		3.4
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.8
Varity_R		0.58
gMVP		0.94

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

Publications

LitVar

Other links and lift over

dbSNP: rs398124648; hg19: chr2-47388887;