2-47171925-C-T

Variant names:

• chr2-47171925-C-T
• rs815815
• NM_001743.6:c.4-1161G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001305626.1(CALM2):​c.-1266G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.863 in 150,062 control chromosomes in the GnomAD database, including 55,888 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.86 (55878 hom., cov: 24)
  • Exomes 𝑓: 0.83 (10 hom.)
• Consequence: CALM2 NM_001305626.1 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.65
• Publications: 18 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.897 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001305626.1. 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.4-1161G>A		intron	N/A	NP_001734.1	P0DP24
	CALM2	NM_001305626.1		c.-1266G>A		5_prime_UTR	Exon 1 of 5	NP_001292555.1	Q96HY3
	CALM2	NM_001305624.1		c.147+489G>A		intron	N/A	NP_001292553.1	P0DP24

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CALM2	ENST00000272298.12	TSL:1 MANE Select	c.4-1161G>A		intron	N/A	ENSP00000272298.7	P0DP24
	CALM2	ENST00000460218.5	TSL:1	n.2283G>A		non_coding_transcript_exon	Exon 1 of 5
	ENSG00000273269	ENST00000422269.1	TSL:2	n.70-1161G>A		intron	N/A	ENSP00000476793.1	V9GYI7

Frequencies

GnomAD3 genomes AF: 0.863 AC: 129410 AN: 149920 Hom.: 55825 Cov.: 24

Gnomad AFR AF: 0.839

Gnomad AMI AF: 0.861

Gnomad AMR AF: 0.894

Gnomad ASJ AF: 0.933

Gnomad EAS AF: 0.878

Gnomad SAS AF: 0.919

Gnomad FIN AF: 0.849

Gnomad MID AF: 0.913

Gnomad NFE AF: 0.864

Gnomad OTH AF: 0.876

GnomAD4 exome AF: 0.833 AC: 25 AN: 30 Hom.: 10 Cov.: 0 AF XY: 0.818 AC XY: 18 AN XY: 22

African (AFR) AF: 1.00 AC: 2 AN: 2

American (AMR) AF: 0.750 AC: 3 AN: 4

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 1.00 AC: 2 AN: 2

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.818 AC: 18 AN: 22

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.863 AC: 129518 AN: 150032 Hom.: 55878 Cov.: 24 AF XY: 0.865 AC XY: 63313 AN XY: 73160

African (AFR) AF: 0.839 AC: 33972 AN: 40478

American (AMR) AF: 0.894 AC: 13493 AN: 15098

Ashkenazi Jewish (ASJ) AF: 0.933 AC: 3232 AN: 3464

East Asian (EAS) AF: 0.878 AC: 4473 AN: 5096

South Asian (SAS) AF: 0.919 AC: 4382 AN: 4766

European-Finnish (FIN) AF: 0.849 AC: 8543 AN: 10060

Middle Eastern (MID) AF: 0.921 AC: 267 AN: 290

European-Non Finnish (NFE) AF: 0.864 AC: 58546 AN: 67786

Other (OTH) AF: 0.876 AC: 1828 AN: 2086

Alfa AF: 0.865 Hom.: 104701

Bravo AF: 0.861

Asia WGS AF: 0.895 AC: 3108 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.34
DANN	Benign	0.34
PhyloP100		-4.6
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: rs815815; hg19: chr2-47399064;