2-47161648-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001743.6(CALM2):c.421+75C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0154 in 1,384,854 control chromosomes in the GnomAD database, including 206 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.012 (23 hom., cov: 31)
  • Exomes 𝑓: 0.016 (183 hom.)
• Consequence: CALM2 NM_001743.6 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.603

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 2-47161648-G-C is Benign according to our data. Variant chr2-47161648-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 1214286.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0122 (1858/152188) while in subpopulation NFE AF= 0.0166 (1128/68002). AF 95% confidence interval is 0.0158. There are 23 homozygotes in gnomad4. There are 907 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd at 1860 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CALM2	NM_001743.6	c.421+75C>G		intron_variant		ENST00000272298.12
CALM2	NM_001305624.1	c.565+75C>G		intron_variant
CALM2	NM_001305625.2	c.313+75C>G		intron_variant
CALM2	NM_001305626.1	c.313+75C>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CALM2	ENST00000272298.12	c.421+75C>G		intron_variant		1	NM_001743.6	P1

Frequencies

GnomAD3 genomes AF: 0.0122 AC: 1860 AN: 152070 Hom.: 23 Cov.: 31

Gnomad AFR AF: 0.00338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00792

Gnomad ASJ AF: 0.00778

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00788

Gnomad FIN AF: 0.0352

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0166

Gnomad OTH AF: 0.0125

GnomAD4 exome AF: 0.0158 AC: 19481 AN: 1232666 Hom.: 183 AF XY: 0.0157 AC XY: 9605 AN XY: 613116

Gnomad4 AFR exome AF: 0.00238

Gnomad4 AMR exome AF: 0.00809

Gnomad4 ASJ exome AF: 0.00535

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0101

Gnomad4 FIN exome AF: 0.0328

Gnomad4 NFE exome AF: 0.0168

Gnomad4 OTH exome AF: 0.0150

GnomAD4 genome AF: 0.0122 AC: 1858 AN: 152188 Hom.: 23 Cov.: 31 AF XY: 0.0122 AC XY: 907 AN XY: 74382

Gnomad4 AFR AF: 0.00337

Gnomad4 AMR AF: 0.00791

Gnomad4 ASJ AF: 0.00778

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00788

Gnomad4 FIN AF: 0.0352

Gnomad4 NFE AF: 0.0166

Gnomad4 OTH AF: 0.0123

Alfa AF: 0.00526 Hom.: 0

Bravo AF: 0.0102

Asia WGS AF: 0.00289 AC: 10 AN: 3478

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

Jun 28, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
Cadd	Benign	0.48
Dann	Benign	0.38
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: rs3729956; hg19: chr2-47388787;