chr2-47161627-A-G

Position:

• chr2-47161627-A-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+96T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.854 in 1,095,924 control chromosomes in the GnomAD database, including 396,029 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.75 (44627 hom., cov: 31)
  • Exomes 𝑓: 0.87 (351402 hom.)
• Consequence: CALM2 NM_001743.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.903

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=-1.0).
• BP6: Variant 2-47161627-A-G is Benign according to our data. Variant chr2-47161627-A-G is described in ClinVar as [Benign]. Clinvar id is 674615.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.915 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CALM2	NM_001743.6	c.421+96T>C		intron_variant		ENST00000272298.12	NP_001734.1
CALM2	NM_001305624.1	c.565+96T>C		intron_variant			NP_001292553.1
CALM2	NM_001305625.2	c.313+96T>C		intron_variant			NP_001292554.1
CALM2	NM_001305626.1	c.313+96T>C		intron_variant			NP_001292555.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CALM2	ENST00000272298.12	c.421+96T>C		intron_variant		1	NM_001743.6	ENSP00000272298	P1

Frequencies

GnomAD3 genomes AF: 0.751 AC: 114064 AN: 151948 Hom.: 44613 Cov.: 31

Gnomad AFR AF: 0.511

Gnomad AMI AF: 0.777

Gnomad AMR AF: 0.779

Gnomad ASJ AF: 0.899

Gnomad EAS AF: 0.937

Gnomad SAS AF: 0.765

Gnomad FIN AF: 0.856

Gnomad MID AF: 0.845

Gnomad NFE AF: 0.849

Gnomad OTH AF: 0.782

GnomAD4 exome AF: 0.871 AC: 822119 AN: 943858 Hom.: 351402 AF XY: 0.870 AC XY: 415057 AN XY: 476860

Gnomad4 AFR exome AF: 0.686

Gnomad4 AMR exome AF: 0.814

Gnomad4 ASJ exome AF: 0.904

Gnomad4 EAS exome AF: 0.939

Gnomad4 SAS exome AF: 0.832

Gnomad4 FIN exome AF: 0.873

Gnomad4 NFE exome AF: 0.876

Gnomad4 OTH exome AF: 0.867

GnomAD4 genome AF: 0.750 AC: 114119 AN: 152066 Hom.: 44627 Cov.: 31 AF XY: 0.754 AC XY: 56044 AN XY: 74346

Gnomad4 AFR AF: 0.511

Gnomad4 AMR AF: 0.778

Gnomad4 ASJ AF: 0.899

Gnomad4 EAS AF: 0.937

Gnomad4 SAS AF: 0.765

Gnomad4 FIN AF: 0.856

Gnomad4 NFE AF: 0.849

Gnomad4 OTH AF: 0.785

Alfa AF: 0.960 Hom.: 8062

Bravo AF: 0.969

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	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
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. -

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	0.12
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: rs2454085; hg19: chr2-47388766;