2-47160792-A-C

Variant names:

• chr2-47160792-A-C
• rs1558693760
• NM_001743.6:c.434T>G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 PP5_Moderate

The NM_001743.6(CALM2):​c.434T>G​(p.Met145Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CALM2 NM_001743.6 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.32

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]

ENSG00000273269 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• 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 long QT syndrome, long QT syndrome 15, catecholaminergic polymorphic ventricular tachycardia.
• PP5: Variant 2-47160792-A-C is Pathogenic according to our data. Variant chr2-47160792-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 576319.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.434T>G	p.Met145Arg	missense_variant	Exon 6 of 6	ENST00000272298.12	NP_001734.1
CALM2	NM_001305624.1	c.578T>G	p.Met193Arg	missense_variant	Exon 7 of 7		NP_001292553.1
CALM2	NM_001305625.2	c.326T>G	p.Met109Arg	missense_variant	Exon 6 of 6		NP_001292554.1
CALM2	NM_001305626.1	c.326T>G	p.Met109Arg	missense_variant	Exon 5 of 5		NP_001292555.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CALM2	ENST00000272298.12	c.434T>G	p.Met145Arg	missense_variant	Exon 6 of 6	1	NM_001743.6	ENSP00000272298.7
ENSG00000273269	ENST00000422269.1	n.101-7776T>G		intron_variant	Intron 2 of 8	2		ENSP00000476793.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 21

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Long QT syndrome 1 Pathogenic:1

Jun 04, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has been observed to be de novo in individuals affected with CALM2-related clinical features (Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change replaces methionine with arginine at codon 145 of the CALM2 protein (p.Met145Arg). The methionine residue is moderately conserved and there is a moderate physicochemical difference between methionine and arginine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	27
DANN	Benign	0.95
DEOGEN2	Benign	0.33	.;.;T;.
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D;.;D
M_CAP	Uncertain	0.27	D
MetaRNN	Uncertain	0.62	D;D;D;D
MetaSVM	Benign	-0.29	T
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-2.7	D;.;D;D
REVEL	Uncertain	0.44
Sift	Pathogenic	0.0	.;.;D;D
Sift4G	Uncertain	0.058	T;T;D;D
Vest4		0.83
MutPred		0.35		Gain of MoRF binding (P = 0.0016);.;.;.;
MVP		0.41
MPC		3.1
ClinPred		0.96	D
GERP RS		6.0
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		3.8
Varity_R		0.90
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs1558693760; hg19: chr2-47387931;