rs2454084

Variant names:

• chr2-47161626-C-G
• rs2454084
• NM_001743.6:c.421+97G>C

Your query was ambiguous. Multiple possible variants found:

• chr2-47161626-C-G
• chr2-47161626-C-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001743.6(CALM2):​c.421+97G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.801 in 1,040,338 control chromosomes in the GnomAD database, including 321,512 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.77 (36381 hom., cov: 29)
  • Exomes 𝑓: 0.81 (285131 hom.)
• Consequence: CALM2 NM_001743.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• 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: 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.03).
• BP6: Variant 2-47161626-C-G is Benign according to our data. Variant chr2-47161626-C-G is described in ClinVar as Benign. ClinVar VariationId is 674616.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.847 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+97G>C		intron	N/A	NP_001734.1	P0DP24
	CALM2	NM_001305624.1		c.565+97G>C		intron	N/A	NP_001292553.1	P0DP24
	CALM2	NM_001305625.2		c.313+97G>C		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+97G>C		intron	N/A	ENSP00000272298.7	P0DP24
	ENSG00000273269	ENST00000422269.1	TSL:2	n.101-8610G>C		intron	N/A	ENSP00000476793.1	V9GYI7
	CALM2	ENST00000460218.5	TSL:1	n.3861+97G>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.766 AC: 101575 AN: 132530 Hom.: 36364 Cov.: 29

Gnomad AFR AF: 0.612

Gnomad AMI AF: 0.759

Gnomad AMR AF: 0.768

Gnomad ASJ AF: 0.881

Gnomad EAS AF: 0.869

Gnomad SAS AF: 0.773

Gnomad FIN AF: 0.826

Gnomad MID AF: 0.815

Gnomad NFE AF: 0.806

Gnomad OTH AF: 0.763

GnomAD4 exome AF: 0.806 AC: 731696 AN: 907752 Hom.: 285131 AF XY: 0.807 AC XY: 370573 AN XY: 459464

African (AFR) AF: 0.617 AC: 8169 AN: 13240

American (AMR) AF: 0.751 AC: 16578 AN: 22074

Ashkenazi Jewish (ASJ) AF: 0.872 AC: 14955 AN: 17156

East Asian (EAS) AF: 0.867 AC: 29447 AN: 33976

South Asian (SAS) AF: 0.787 AC: 40869 AN: 51936

European-Finnish (FIN) AF: 0.821 AC: 38425 AN: 46824

Middle Eastern (MID) AF: 0.854 AC: 2466 AN: 2888

European-Non Finnish (NFE) AF: 0.808 AC: 549068 AN: 679938

Other (OTH) AF: 0.799 AC: 31719 AN: 39720

GnomAD4 genome AF: 0.766 AC: 101619 AN: 132586 Hom.: 36381 Cov.: 29 AF XY: 0.770 AC XY: 50065 AN XY: 65042

African (AFR) AF: 0.612 AC: 16486 AN: 26942

American (AMR) AF: 0.768 AC: 10733 AN: 13984

Ashkenazi Jewish (ASJ) AF: 0.881 AC: 3011 AN: 3416

East Asian (EAS) AF: 0.869 AC: 4431 AN: 5100

South Asian (SAS) AF: 0.774 AC: 3398 AN: 4392

European-Finnish (FIN) AF: 0.826 AC: 8432 AN: 10212

Middle Eastern (MID) AF: 0.830 AC: 239 AN: 288

European-Non Finnish (NFE) AF: 0.806 AC: 52749 AN: 65446

Other (OTH) AF: 0.764 AC: 1481 AN: 1938

Alfa AF: 0.838 Hom.: 1308

Bravo AF: 0.883

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Long QT syndrome 15 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.021
DANN	Benign	0.36
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: rs2454084; hg19: chr2-47388765;