chr2-47160824-C-A

Variant names:

• chr2-47160824-C-A
• rs1024594334
• NM_001743.6:c.422-20G>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.422-20G>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: 0)
  • Exomes 𝑓: 0.00013 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CALM2 NM_001743.6 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.57
• 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: G2P, Labcorp Genetics (formerly Invitae)
• catecholaminergic polymorphic ventricular tachycardia

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Genomics England PanelApp, ClinGen, G2P

ENSG00000273269 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 2-47160824-C-A is Benign according to our data. Variant chr2-47160824-C-A is described in ClinVar as Likely_benign. ClinVar VariationId is 3702689.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.422-20G>T		intron	N/A	NP_001734.1	P0DP24
	CALM2	NM_001305624.1		c.566-20G>T		intron	N/A	NP_001292553.1	P0DP24
	CALM2	NM_001305625.2		c.314-20G>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.422-20G>T		intron	N/A	ENSP00000272298.7	P0DP24
	ENSG00000273269	ENST00000422269.1	TSL:2	n.101-7808G>T		intron	N/A	ENSP00000476793.1	V9GYI7
	CALM2	ENST00000460218.5	TSL:1	n.3862-20G>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 46662 Hom.: 0 Cov.: 0

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: 0.0000121 AC: 1 AN: 82420 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000176

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 Data not reliable, filtered out with message: AS_VQSR AF: 0.000133 AC: 78 AN: 586088 Hom.: 0 Cov.: 15 AF XY: 0.000133 AC XY: 39 AN XY: 293412

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000986 AC: 1 AN: 10142

American (AMR) AF: 0.00 AC: 0 AN: 12394

Ashkenazi Jewish (ASJ) AF: 0.000144 AC: 2 AN: 13856

East Asian (EAS) AF: 0.00 AC: 0 AN: 21314

South Asian (SAS) AF: 0.000376 AC: 8 AN: 21252

European-Finnish (FIN) AF: 0.0000597 AC: 2 AN: 33504

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1980

European-Non Finnish (NFE) AF: 0.000141 AC: 63 AN: 446970

Other (OTH) AF: 0.0000811 AC: 2 AN: 24676

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 46702 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 22508

African (AFR) AF: 0.00 AC: 0 AN: 9590

American (AMR) AF: 0.00 AC: 0 AN: 4018

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1408

East Asian (EAS) AF: 0.00 AC: 0 AN: 2166

South Asian (SAS) AF: 0.00 AC: 0 AN: 1630

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2822

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 64

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 24124

Other (OTH) AF: 0.00 AC: 0 AN: 618

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

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
PhyloP100		-1.6
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1024594334; hg19: chr2-47387963; COSMIC: COSV55400173; COSMIC: COSV55400173;