2-47174925-G-C

Variant names:

• chr2-47174925-G-C
• rs1693869
• NM_001743.6:c.3+1516C>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001743.6(CALM2):​c.3+1516C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.889 in 151,998 control chromosomes in the GnomAD database, including 60,045 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.89 (60045 hom., cov: 28)
• Consequence: CALM2 NM_001743.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.101
• 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.9 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001743.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CALM2	NM_001743.6	MANE Select	c.3+1516C>G		intron	N/A	NP_001734.1
	CALM2	NM_001305624.1		c.101+1516C>G		intron	N/A	NP_001292553.1
	CALM2	NM_001305625.2		c.-106+1924C>G		intron	N/A	NP_001292554.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CALM2	ENST00000272298.12	TSL:1 MANE Select	c.3+1516C>G		intron	N/A	ENSP00000272298.7
	ENSG00000273269	ENST00000422269.1	TSL:2	n.69+1516C>G		intron	N/A	ENSP00000476793.1
	CALM2	ENST00000409563.5	TSL:5	c.-72+1516C>G		intron	N/A	ENSP00000387065.1

Frequencies

GnomAD3 genomes AF: 0.888 AC: 134943 AN: 151880 Hom.: 59983 Cov.: 28

Gnomad AFR AF: 0.888

Gnomad AMI AF: 0.875

Gnomad AMR AF: 0.902

Gnomad ASJ AF: 0.933

Gnomad EAS AF: 0.918

Gnomad SAS AF: 0.923

Gnomad FIN AF: 0.901

Gnomad MID AF: 0.921

Gnomad NFE AF: 0.876

Gnomad OTH AF: 0.894

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.889 AC: 135064 AN: 151998 Hom.: 60045 Cov.: 28 AF XY: 0.891 AC XY: 66218 AN XY: 74302

African (AFR) AF: 0.888 AC: 36796 AN: 41414

American (AMR) AF: 0.902 AC: 13775 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.933 AC: 3239 AN: 3470

East Asian (EAS) AF: 0.918 AC: 4748 AN: 5170

South Asian (SAS) AF: 0.923 AC: 4444 AN: 4814

European-Finnish (FIN) AF: 0.901 AC: 9523 AN: 10570

Middle Eastern (MID) AF: 0.929 AC: 273 AN: 294

European-Non Finnish (NFE) AF: 0.877 AC: 59579 AN: 67970

Other (OTH) AF: 0.895 AC: 1891 AN: 2114

Alfa AF: 0.888 Hom.: 7450

Bravo AF: 0.887

Asia WGS AF: 0.923 AC: 3207 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	10
DANN	Benign	0.69
PhyloP100		-0.10
Mutation Taster		=100/0	polymorphism (auto)

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: rs1693869; hg19: chr2-47402064;