2-47171925-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001743.6(CALM2):c.4-1161G>A variant causes a intron 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_001743.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.65

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]

ACMG classification

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CALM2	NM_001743.6	c.4-1161G>A		intron_variant		ENST00000272298.12
CALM2	NM_001305626.1	c.-1266G>A		5_prime_UTR_variant	1/5
CALM2	NM_001305624.1	c.147+489G>A		intron_variant
CALM2	NM_001305625.2	c.-105-1161G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CALM2	ENST00000272298.12	c.4-1161G>A		intron_variant		1	NM_001743.6	P1

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

Gnomad4 AFR exome AF: 1.00

Gnomad4 AMR exome AF: 0.750

Gnomad4 EAS exome AF: 1.00

Gnomad4 NFE exome AF: 0.818

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

Gnomad4 AFR AF: 0.839

Gnomad4 AMR AF: 0.894

Gnomad4 ASJ AF: 0.933

Gnomad4 EAS AF: 0.878

Gnomad4 SAS AF: 0.919

Gnomad4 FIN AF: 0.849

Gnomad4 NFE AF: 0.864

Gnomad4 OTH AF: 0.876

Alfa AF: 0.866 Hom.: 58402

Bravo AF: 0.861

Asia WGS AF: 0.895 AC: 3108 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
Cadd	Benign	0.34
Dann	Benign	0.34

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

Publications

LitVar

Other links and lift over

dbSNP: rs815815; hg19: chr2-47399064;