2-47161626-C-G

Position:

• chr2-47161626-C-G

Variant summary

Our verdict is Benign. Variant got -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

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 -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CALM2	NM_001743.6	c.421+97G>C		intron_variant		ENST00000272298.12	NP_001734.1
CALM2	NM_001305624.1	c.565+97G>C		intron_variant			NP_001292553.1
CALM2	NM_001305625.2	c.313+97G>C		intron_variant			NP_001292554.1
CALM2	NM_001305626.1	c.313+97G>C		intron_variant			NP_001292555.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CALM2	ENST00000272298.12	c.421+97G>C		intron_variant		1	NM_001743.6	ENSP00000272298	P1

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

Gnomad4 AFR exome AF: 0.617

Gnomad4 AMR exome AF: 0.751

Gnomad4 ASJ exome AF: 0.872

Gnomad4 EAS exome AF: 0.867

Gnomad4 SAS exome AF: 0.787

Gnomad4 FIN exome AF: 0.821

Gnomad4 NFE exome AF: 0.808

Gnomad4 OTH exome AF: 0.799

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

Gnomad4 AFR AF: 0.612

Gnomad4 AMR AF: 0.768

Gnomad4 ASJ AF: 0.881

Gnomad4 EAS AF: 0.869

Gnomad4 SAS AF: 0.774

Gnomad4 FIN AF: 0.826

Gnomad4 NFE AF: 0.806

Gnomad4 OTH AF: 0.764

Alfa AF: 0.838 Hom.: 1308

Bravo AF: 0.883

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 14, 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. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Long QT syndrome 15 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.021
DANN	Benign	0.36

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: rs2454084; hg19: chr2-47388765;