2-47162328-G-A

Position:

• chr2-47162328-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Moderate BP6_Very_Strong BS2

The NM_001743.6(CALM2):​c.243C>T​(p.Asp81Asp) variant causes a synonymous change. The variant allele was found at a frequency of 0.000742 in 1,612,308 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00059 (1 hom., cov: 31)
  • Exomes 𝑓: 0.00076 (2 hom.)
• Consequence: CALM2 NM_001743.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 4.22

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]

CALM2 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 2-47162328-G-A is Benign according to our data. Variant chr2-47162328-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 239033.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47162328-G-A is described in Lovd as [Benign].
• BS2: High AC in GnomAd4 at 89 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CALM2	NM_001743.6	c.243C>T	p.Asp81Asp	synonymous_variant	4/6	ENST00000272298.12	NP_001734.1
CALM2	NM_001305624.1	c.387C>T	p.Asp129Asp	synonymous_variant	5/7		NP_001292553.1
CALM2	NM_001305625.2	c.135C>T	p.Asp45Asp	synonymous_variant	4/6		NP_001292554.1
CALM2	NM_001305626.1	c.135C>T	p.Asp45Asp	synonymous_variant	3/5		NP_001292555.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CALM2	ENST00000272298.12	c.243C>T	p.Asp81Asp	synonymous_variant	4/6	1	NM_001743.6	ENSP00000272298.7
ENSG00000273269	ENST00000422269.1	n.100+8406C>T		intron_variant		2		ENSP00000476793.1

Frequencies

GnomAD3 genomes AF: 0.000586 AC: 89 AN: 151892 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000917

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000286

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000868

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000795 AC: 199 AN: 250382 Hom.: 0 AF XY: 0.000850 AC XY: 115 AN XY: 135322

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000320

Gnomad ASJ exome AF: 0.000900

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000362

Gnomad FIN exome AF: 0.000324

Gnomad NFE exome AF: 0.00130

Gnomad OTH exome AF: 0.00180

GnomAD4 exome AF: 0.000759 AC: 1108 AN: 1460304 Hom.: 2 Cov.: 30 AF XY: 0.000769 AC XY: 559 AN XY: 726458

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.000337

Gnomad4 ASJ exome AF: 0.000691

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000570

Gnomad4 FIN exome AF: 0.000281

Gnomad4 NFE exome AF: 0.000850

Gnomad4 OTH exome AF: 0.000812

GnomAD4 genome AF: 0.000586 AC: 89 AN: 152004 Hom.: 1 Cov.: 31 AF XY: 0.000539 AC XY: 40 AN XY: 74268

Gnomad4 AFR AF: 0.000121

Gnomad4 AMR AF: 0.000916

Gnomad4 ASJ AF: 0.000577

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000286

Gnomad4 NFE AF: 0.000868

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000762 Hom.: 0

Bravo AF: 0.000623

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.00125

EpiControl AF: 0.00136

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	CALM2: BP4, BP7 -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 27, 2021	- -

Long QT syndrome 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Clinical Genetics, Academic Medical Center

-

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 10, 2019

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	8.2
DANN	Benign	0.57
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs141298844; hg19: chr2-47389467;