rs815802

chr2-47164910-G-Achr2-47164910-G-C

Variant summary

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

The NM_001743.6(CALM2):c.35-2248C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.898 in 152,192 control chromosomes in the GnomAD database, including 61,413 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 0.90 (61413 hom., cov: 31)
• Consequence: CALM2 NM_001743.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.790

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=-0.86).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.914 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CALM2	NM_001743.6	c.35-2248C>T		intron_variant		ENST00000272298.12
CALM2	NM_001305624.1	c.179-2248C>T		intron_variant
CALM2	NM_001305625.2	c.-74-2248C>T		intron_variant
CALM2	NM_001305626.1	c.-74-2248C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CALM2	ENST00000272298.12	c.35-2248C>T		intron_variant		1	NM_001743.6	P1

Frequencies

GnomAD3 genomes AF: 0.898 AC: 136515 AN: 152074 Hom.: 61354 Cov.: 31

Gnomad AFR AF: 0.896

Gnomad AMI AF: 0.893

Gnomad AMR AF: 0.923

Gnomad ASJ AF: 0.943

Gnomad EAS AF: 0.875

Gnomad SAS AF: 0.935

Gnomad FIN AF: 0.862

Gnomad MID AF: 0.943

Gnomad NFE AF: 0.895

Gnomad OTH AF: 0.909

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

GnomAD4 genome AF: 0.898 AC: 136633 AN: 152192 Hom.: 61413 Cov.: 31 AF XY: 0.898 AC XY: 66822 AN XY: 74402

Gnomad4 AFR AF: 0.896

Gnomad4 AMR AF: 0.923

Gnomad4 ASJ AF: 0.943

Gnomad4 EAS AF: 0.875

Gnomad4 SAS AF: 0.936

Gnomad4 FIN AF: 0.862

Gnomad4 NFE AF: 0.895

Gnomad4 OTH AF: 0.909

Alfa AF: 0.899 Hom.: 89379

Bravo AF: 0.900

Asia WGS AF: 0.907 AC: 3154 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	6.8
Dann	Benign	0.87

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: rs815802; hg19: chr2-47392049;