rs113581500

Variant names:

• chr2-47161625-TCA-T
• rs113581500
• NM_001743.6:c.421+96_421+97delTG

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+96_421+97delTG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.124 in 1,104,254 control chromosomes in the GnomAD database, including 14,446 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.22 (5697 hom., cov: 29)
  • Exomes 𝑓: 0.11 (8749 hom.)
• Consequence: CALM2 NM_001743.6 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.765
• 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: Benign. The variant received -10 ACMG points.

• BP6: Variant 2-47161625-TCA-T is Benign according to our data. Variant chr2-47161625-TCA-T is described in ClinVar as Benign. ClinVar VariationId is 674617.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+96_421+97delTG		intron	N/A	NP_001734.1	P0DP24
	CALM2	NM_001305624.1		c.565+96_565+97delTG		intron	N/A	NP_001292553.1	P0DP24
	CALM2	NM_001305625.2		c.313+96_313+97delTG		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+96_421+97delTG		intron	N/A	ENSP00000272298.7	P0DP24
	ENSG00000273269	ENST00000422269.1	TSL:2	n.101-8611_101-8610delTG		intron	N/A	ENSP00000476793.1	V9GYI7
	CALM2	ENST00000460218.5	TSL:1	n.3861+96_3861+97delTG		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.216 AC: 32787 AN: 151680 Hom.: 5679 Cov.: 29

Gnomad AFR AF: 0.480

Gnomad AMI AF: 0.143

Gnomad AMR AF: 0.199

Gnomad ASJ AF: 0.0621

Gnomad EAS AF: 0.0625

Gnomad SAS AF: 0.219

Gnomad FIN AF: 0.101

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.0993

Gnomad OTH AF: 0.189

GnomAD4 exome AF: 0.109 AC: 103556 AN: 952454 Hom.: 8749 AF XY: 0.110 AC XY: 52790 AN XY: 481958

African (AFR) AF: 0.483 AC: 10135 AN: 20968

American (AMR) AF: 0.223 AC: 5583 AN: 24992

Ashkenazi Jewish (ASJ) AF: 0.0608 AC: 1060 AN: 17430

East Asian (EAS) AF: 0.0642 AC: 2237 AN: 34862

South Asian (SAS) AF: 0.194 AC: 10971 AN: 56556

European-Finnish (FIN) AF: 0.104 AC: 5052 AN: 48450

Middle Eastern (MID) AF: 0.0907 AC: 268 AN: 2954

European-Non Finnish (NFE) AF: 0.0896 AC: 63130 AN: 704296

Other (OTH) AF: 0.122 AC: 5120 AN: 41946

GnomAD4 genome AF: 0.216 AC: 32856 AN: 151800 Hom.: 5697 Cov.: 29 AF XY: 0.214 AC XY: 15879 AN XY: 74196

African (AFR) AF: 0.480 AC: 19870 AN: 41414

American (AMR) AF: 0.199 AC: 3030 AN: 15216

Ashkenazi Jewish (ASJ) AF: 0.0621 AC: 215 AN: 3460

East Asian (EAS) AF: 0.0626 AC: 324 AN: 5172

South Asian (SAS) AF: 0.218 AC: 1047 AN: 4796

European-Finnish (FIN) AF: 0.101 AC: 1070 AN: 10554

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

European-Non Finnish (NFE) AF: 0.0993 AC: 6744 AN: 67882

Other (OTH) AF: 0.187 AC: 393 AN: 2100

Alfa AF: 0.126 Hom.: 30

Asia WGS AF: 0.166 AC: 578 AN: 3478

ClinVar

ClinVar submissions as Germline

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		-0.77
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: rs113581500; hg19: chr2-47388764;