2-47161625-TCA-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_001743.6(CALM2):c.421+96_421+97del 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

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 -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CALM2	NM_001743.6	c.421+96_421+97del		intron_variant		ENST00000272298.12
CALM2	NM_001305624.1	c.565+96_565+97del		intron_variant
CALM2	NM_001305625.2	c.313+96_313+97del		intron_variant
CALM2	NM_001305626.1	c.313+96_313+97del		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CALM2	ENST00000272298.12	c.421+96_421+97del		intron_variant		1	NM_001743.6	P1

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

Gnomad4 AFR exome AF: 0.483

Gnomad4 AMR exome AF: 0.223

Gnomad4 ASJ exome AF: 0.0608

Gnomad4 EAS exome AF: 0.0642

Gnomad4 SAS exome AF: 0.194

Gnomad4 FIN exome AF: 0.104

Gnomad4 NFE exome AF: 0.0896

Gnomad4 OTH exome AF: 0.122

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

Gnomad4 AFR AF: 0.480

Gnomad4 AMR AF: 0.199

Gnomad4 ASJ AF: 0.0621

Gnomad4 EAS AF: 0.0626

Gnomad4 SAS AF: 0.218

Gnomad4 FIN AF: 0.101

Gnomad4 NFE AF: 0.0993

Gnomad4 OTH AF: 0.187

Alfa AF: 0.126 Hom.: 30

Asia WGS AF: 0.166 AC: 578 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 19, 2018

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

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: rs113581500; hg19: chr2-47388764;