2-47161744-C-T

Position:

• chr2-47161744-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP2 PP3 PP5

The NM_001743.6(CALM2):​c.400G>A​(p.Asp134Asn) 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: 7.87

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a binding_site (size 0) in uniprot entity CALM2_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CALM2. . Gene score misZ 2.7928 (greater than the threshold 3.09). Trascript score misZ 3.5506 (greater than threshold 3.09). GenCC has associacion of gene with long QT syndrome, long QT syndrome 15, catecholaminergic polymorphic ventricular tachycardia.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.839
• PP5: Variant 2-47161744-C-T is Pathogenic according to our data. Variant chr2-47161744-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 448971.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CALM2	NM_001743.6	c.400G>A	p.Asp134Asn	missense_variant	5/6	ENST00000272298.12	NP_001734.1
CALM2	NM_001305624.1	c.544G>A	p.Asp182Asn	missense_variant	6/7		NP_001292553.1
CALM2	NM_001305625.2	c.292G>A	p.Asp98Asn	missense_variant	5/6		NP_001292554.1
CALM2	NM_001305626.1	c.292G>A	p.Asp98Asn	missense_variant	4/5		NP_001292555.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CALM2	ENST00000272298.12	c.400G>A	p.Asp134Asn	missense_variant	5/6	1	NM_001743.6	ENSP00000272298.7
ENSG00000273269	ENST00000422269.1	n.101-8728G>A		intron_variant		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 15 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues

Jun 09, 2017

- -

Long QT syndrome 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 10, 2022

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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant disrupts the p.Asp134 amino acid residue in CALM2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24917665). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 448971). This missense change has been observed in individuals with long QT syndrome (PMID: 32383558; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 134 of the CALM2 protein (p.Asp134Asn). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.082	D
BayesDel_noAF	Benign	-0.12
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Benign	0.30	.;.;T;.
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.83	T;T;.;T
M_CAP	Pathogenic	0.56	D
MetaRNN	Pathogenic	0.84	D;D;D;D
MetaSVM	Uncertain	0.31	D
PrimateAI	Pathogenic	0.92	D
PROVEAN	Uncertain	-3.1	D;.;D;D
REVEL	Pathogenic	0.77
Sift	Uncertain	0.014	.;.;D;D
Sift4G	Uncertain	0.056	T;T;D;T
Vest4		0.75
MutPred		0.78		Loss of disorder (P = 0.1365);.;.;.;
MVP		0.91
MPC		1.9
ClinPred		0.96	D
GERP RS		5.7
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.8
Varity_R		0.74
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.48		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.48		Position offset: 3

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

Publications

LitVar

Other links and lift over

dbSNP: rs398124650; hg19: chr2-47388883;