2-47160810-AAAG-A

Position:

• chr2-47160810-AAAG-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP6_Very_Strong BS2

The NM_001743.6(CALM2):​c.422-9_422-7del variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000748 in 1,484,440 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 0)
  • Exomes 𝑓: 0.000068 (0 hom.)
• Consequence: CALM2 NM_001743.6 splice_region, splice_polypyrimidine_tract, intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.99

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 -12 ACMG points.

• BP6: Variant 2-47160810-AAAG-A is Benign according to our data. Variant chr2-47160810-AAAG-A is described in ClinVar as [Likely_benign]. Clinvar id is 415527.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 21 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CALM2	NM_001743.6	c.422-9_422-7del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000272298.12	NP_001734.1
CALM2	NM_001305624.1	c.566-9_566-7del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NP_001292553.1
CALM2	NM_001305625.2	c.314-9_314-7del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NP_001292554.1
CALM2	NM_001305626.1	c.314-9_314-7del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NP_001292555.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CALM2	ENST00000272298.12	c.422-9_422-7del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_001743.6	ENSP00000272298	P1

Frequencies

GnomAD3 genomes AF: 0.000139 AC: 21 AN: 151190 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.0000971

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000195

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000236

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000442 AC: 7 AN: 158268 Hom.: 0 AF XY: 0.0000118 AC XY: 1 AN XY: 85034

Gnomad AFR exome AF: 0.0000923

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000675 AC: 90 AN: 1333250 Hom.: 0 AF XY: 0.0000650 AC XY: 43 AN XY: 661874

Gnomad4 AFR exome AF: 0.000135

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000265

Gnomad4 SAS exome AF: 0.0000139

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000739

Gnomad4 OTH exome AF: 0.0000544

GnomAD4 genome AF: 0.000139 AC: 21 AN: 151190 Hom.: 0 Cov.: 0 AF XY: 0.000122 AC XY: 9 AN XY: 73758

Gnomad4 AFR AF: 0.0000971

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000195

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000236

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000253 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Long QT syndrome 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

May 19, 2022

See Variant Classification Assertion Criteria. -

Computational scores

Source: dbNSFP v4.3

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: rs775247848; hg19: chr2-47387949;