2-47160847-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001743.6(CALM2):c.422-43C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00074 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0016 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CALM2 NM_001743.6 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.234

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.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 2-47160847-G-A is Benign according to our data. Variant chr2-47160847-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1218759.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAdExome at 33 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CALM2	NM_001743.6	c.422-43C>T		intron_variant		ENST00000272298.12
CALM2	NM_001305624.1	c.566-43C>T		intron_variant
CALM2	NM_001305625.2	c.314-43C>T		intron_variant
CALM2	NM_001305626.1	c.314-43C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CALM2	ENST00000272298.12	c.422-43C>T		intron_variant		1	NM_001743.6	P1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 21 AN: 28400 Hom.: 0 Cov.: 0 FAILED QC

Gnomad AFR AF: 0.00142

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000990

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000485

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00916 AC: 33 AN: 3602 Hom.: 0 AF XY: 0.0103 AC XY: 14 AN XY: 1360

Gnomad AFR exome AF: 0.00951

Gnomad AMR exome AF: 0.0288

Gnomad ASJ exome AF: 0.0164

Gnomad EAS exome AF: 0.00654

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00467

Gnomad NFE exome AF: 0.00945

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00157 AC: 398 AN: 253806 Hom.: 0 Cov.: 7 AF XY: 0.00196 AC XY: 252 AN XY: 128812

Gnomad4 AFR exome AF: 0.000809

Gnomad4 AMR exome AF: 0.00157

Gnomad4 ASJ exome AF: 0.000853

Gnomad4 EAS exome AF: 0.000355

Gnomad4 SAS exome AF: 0.0196

Gnomad4 FIN exome AF: 0.00144

Gnomad4 NFE exome AF: 0.00127

Gnomad4 OTH exome AF: 0.000990

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000739 AC: 21 AN: 28414 Hom.: 0 Cov.: 0 AF XY: 0.000913 AC XY: 12 AN XY: 13140

Gnomad4 AFR AF: 0.00142

Gnomad4 AMR AF: 0.000988

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000942

Gnomad4 NFE AF: 0.000485

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 20, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	0.85
Dann	Benign	0.42

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: rs756177494; hg19: chr2-47387986;