NM_001743.6:c.422-15C>T

Variant names:

• chr2-47160819-G-A
• rs1278362133
• NM_001743.6:c.422-15C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_001743.6(CALM2):​c.422-15C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 24)
  • Exomes 𝑓: 0.0000050 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CALM2 NM_001743.6 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0280
• 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: G2P, Genomics England PanelApp, ClinGen

ENSG00000273269 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 2-47160819-G-A is Benign according to our data. Variant chr2-47160819-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 2191629.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CALM2	NM_001743.6	MANE Select	c.422-15C>T		intron	N/A	NP_001734.1	P0DP24
	CALM2	NM_001305624.1		c.566-15C>T		intron	N/A	NP_001292553.1	P0DP24
	CALM2	NM_001305625.2		c.314-15C>T		intron	N/A	NP_001292554.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CALM2	ENST00000272298.12	TSL:1 MANE Select	c.422-15C>T		intron	N/A	ENSP00000272298.7	P0DP24
	ENSG00000273269	ENST00000422269.1	TSL:2	n.101-7803C>T		intron	N/A	ENSP00000476793.1	V9GYI7
	CALM2	ENST00000460218.5	TSL:1	n.3862-15C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 81946 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00 AC: 0 AN: 96336 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000504 AC: 4 AN: 793078 Hom.: 0 Cov.: 18 AF XY: 0.00000767 AC XY: 3 AN XY: 390902

African (AFR) AF: 0.00 AC: 0 AN: 14440

American (AMR) AF: 0.00 AC: 0 AN: 16182

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15724

East Asian (EAS) AF: 0.00 AC: 0 AN: 23980

South Asian (SAS) AF: 0.00 AC: 0 AN: 27196

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35126

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2398

European-Non Finnish (NFE) AF: 0.00000639 AC: 4 AN: 626210

Other (OTH) AF: 0.00 AC: 0 AN: 31822

GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 81946 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 38802

African (AFR) AF: 0.00 AC: 0 AN: 18230

American (AMR) AF: 0.00 AC: 0 AN: 7366

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2272

East Asian (EAS) AF: 0.00 AC: 0 AN: 3326

South Asian (SAS) AF: 0.00 AC: 0 AN: 2706

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4504

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 136

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 41806

Other (OTH) AF: 0.00 AC: 0 AN: 1096

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Long QT syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	15
DANN	Benign	0.45
PhyloP100		-0.028
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs1278362133; hg19: chr2-47387958;