chr2-47161857-T-A

Position:

• chr2-47161857-T-A

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Very_Strong

The ENST00000272298.12(CALM2):​c.287A>T​(p.Asp96Val) variant causes a missense, splice region 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. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D96Y) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: CALM2 ENST00000272298.12 missense, splice_region
• Scores: Splicing: ADA: 0.7621
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.98

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 17 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in ENST00000272298.12
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-47161858-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 641544.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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, 0.927
• PP5: Variant 2-47161857-T-A is Pathogenic according to our data. Variant chr2-47161857-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 183233.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CALM2	NM_001743.6	c.287A>T	p.Asp96Val	missense_variant, splice_region_variant	5/6	ENST00000272298.12	NP_001734.1
CALM2	NM_001305624.1	c.431A>T	p.Asp144Val	missense_variant, splice_region_variant	6/7		NP_001292553.1
CALM2	NM_001305625.2	c.179A>T	p.Asp60Val	missense_variant, splice_region_variant	5/6		NP_001292554.1
CALM2	NM_001305626.1	c.179A>T	p.Asp60Val	missense_variant, splice_region_variant	4/5		NP_001292555.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CALM2	ENST00000272298.12	c.287A>T	p.Asp96Val	missense_variant, splice_region_variant	5/6	1	NM_001743.6	ENSP00000272298	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Long QT syndrome 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 26, 2021

This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 96 of the CALM2 protein (p.Asp96Val). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Asp96 amino acid residue in CALM2. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Experimental studies have shown that this missense change affects CALM2 function (PMID: 23388215). 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. ClinVar contains an entry for this variant (Variation ID: 183233). This missense change has been observed in individual(s) with long QT syndrome (PMID: 23388215). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). -

Long QT syndrome 15 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 05, 2013

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Apr 07, 2021

Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate a damaging effect as this variant results in decreased calcium affinity in the C-domain of the protein (Crotti et al., 2013; Sondergaard et al., 2015); This variant is associated with the following publications: (PMID: 30348784, 24563457, 27927985, 27516456, 27815504, 26164367, 24958779, 24816216, 26969752, 23388215, 26309258, 29932249) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	30
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.52	.;D;.
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.76	T;.;T
M_CAP	Pathogenic	0.57	D
MetaRNN	Pathogenic	0.93	D;D;D
MetaSVM	Benign	-0.40	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-8.1	D;D;D
REVEL	Pathogenic	0.77
Sift	Pathogenic	0.0	.;D;D
Sift4G	Uncertain	0.0040	D;D;D
Vest4		0.97
MVP		0.93
MPC		2.9
ClinPred		1.0	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.82
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.76
dbscSNV1_RF	Benign	0.58
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: rs730882254; hg19: chr2-47388996;