chr2-47161627-A-AGGG

Variant names:

• chr2-47161627-A-AGGG
• rs1289216990
• NM_001743.6:c.421+93_421+95dupCCC

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_001743.6(CALM2):​c.421+93_421+95dupCCC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.216 in 152,090 control chromosomes in the GnomAD database, including 5,709 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.22 (5709 hom., cov: 31)
• Consequence: CALM2 NM_001743.6 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0380
• 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: Benign. The variant received -10 ACMG points.

• BP6: Variant 2-47161627-A-AGGG is Benign according to our data. Variant chr2-47161627-A-AGGG is described in ClinVar as Benign. ClinVar VariationId is 1290819.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.474 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CALM2	NM_001743.6	MANE Select	c.421+93_421+95dupCCC		intron	N/A	NP_001734.1	P0DP24
	CALM2	NM_001305624.1		c.565+93_565+95dupCCC		intron	N/A	NP_001292553.1	P0DP24
	CALM2	NM_001305625.2		c.313+93_313+95dupCCC		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.421+95_421+96insCCC		intron	N/A	ENSP00000272298.7	P0DP24
	ENSG00000273269	ENST00000422269.1	TSL:2	n.101-8612_101-8611insCCC		intron	N/A	ENSP00000476793.1	V9GYI7
	CALM2	ENST00000460218.5	TSL:1	n.3861+95_3861+96insCCC		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.216 AC: 32810 AN: 151970 Hom.: 5691 Cov.: 31

Gnomad AFR AF: 0.479

Gnomad AMI AF: 0.143

Gnomad AMR AF: 0.198

Gnomad ASJ AF: 0.0621

Gnomad EAS AF: 0.0623

Gnomad SAS AF: 0.218

Gnomad FIN AF: 0.101

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.0992

Gnomad OTH AF: 0.189

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

GnomAD4 genome AF: 0.216 AC: 32879 AN: 152090 Hom.: 5709 Cov.: 31 AF XY: 0.214 AC XY: 15886 AN XY: 74356

African (AFR) AF: 0.479 AC: 19890 AN: 41482

American (AMR) AF: 0.198 AC: 3029 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.0621 AC: 215 AN: 3462

East Asian (EAS) AF: 0.0624 AC: 324 AN: 5190

South Asian (SAS) AF: 0.217 AC: 1047 AN: 4818

European-Finnish (FIN) AF: 0.101 AC: 1072 AN: 10586

Middle Eastern (MID) AF: 0.112 AC: 33 AN: 294

European-Non Finnish (NFE) AF: 0.0992 AC: 6746 AN: 67970

Other (OTH) AF: 0.187 AC: 393 AN: 2104

Alfa AF: 0.777 Hom.: 30

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.038
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs1289216990; hg19: chr2-47388766;