chr2-47161705-T-C

Position:

• chr2-47161705-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000272298.12(CALM2):​c.421+18A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.019 in 1,603,166 control chromosomes in the GnomAD database, including 1,767 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.021 (174 hom., cov: 30)
  • Exomes 𝑓: 0.019 (1593 hom.)
• Consequence: CALM2 ENST00000272298.12 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.202

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=-0.86).
• BP6: Variant 2-47161705-T-C is Benign according to our data. Variant chr2-47161705-T-C is described in ClinVar as [Benign]. Clinvar id is 384720.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47161705-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.125 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CALM2	NM_001743.6	c.421+18A>G		intron_variant		ENST00000272298.12	NP_001734.1
CALM2	NM_001305624.1	c.565+18A>G		intron_variant			NP_001292553.1
CALM2	NM_001305625.2	c.313+18A>G		intron_variant			NP_001292554.1
CALM2	NM_001305626.1	c.313+18A>G		intron_variant			NP_001292555.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CALM2	ENST00000272298.12	c.421+18A>G		intron_variant		1	NM_001743.6	ENSP00000272298	P1

Frequencies

GnomAD3 genomes AF: 0.0207 AC: 3142 AN: 152150 Hom.: 170 Cov.: 30

Gnomad AFR AF: 0.00430

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.108

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0223

Gnomad SAS AF: 0.133

Gnomad FIN AF: 0.00650

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00654

Gnomad OTH AF: 0.0201

GnomAD3 exomes AF: 0.0463 AC: 11256 AN: 243364 Hom.: 946 AF XY: 0.0446 AC XY: 5875 AN XY: 131674

Gnomad AFR exome AF: 0.00335

Gnomad AMR exome AF: 0.186

Gnomad ASJ exome AF: 0.000508

Gnomad EAS exome AF: 0.0253

Gnomad SAS exome AF: 0.125

Gnomad FIN exome AF: 0.00565

Gnomad NFE exome AF: 0.00677

Gnomad OTH exome AF: 0.0314

GnomAD4 exome AF: 0.0188 AC: 27329 AN: 1450898 Hom.: 1593 Cov.: 30 AF XY: 0.0209 AC XY: 15080 AN XY: 721482

Gnomad4 AFR exome AF: 0.00267

Gnomad4 AMR exome AF: 0.172

Gnomad4 ASJ exome AF: 0.000695

Gnomad4 EAS exome AF: 0.0212

Gnomad4 SAS exome AF: 0.120

Gnomad4 FIN exome AF: 0.00595

Gnomad4 NFE exome AF: 0.00649

Gnomad4 OTH exome AF: 0.0210

GnomAD4 genome AF: 0.0207 AC: 3154 AN: 152268 Hom.: 174 Cov.: 30 AF XY: 0.0238 AC XY: 1775 AN XY: 74462

Gnomad4 AFR AF: 0.00428

Gnomad4 AMR AF: 0.109

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0223

Gnomad4 SAS AF: 0.133

Gnomad4 FIN AF: 0.00650

Gnomad4 NFE AF: 0.00654

Gnomad4 OTH AF: 0.0199

Alfa AF: 0.0129 Hom.: 17

Asia WGS AF: 0.0800 AC: 278 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 10, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 06, 2016	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 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.17
DANN	Benign	0.51
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs2016682; hg19: chr2-47388844;