chr2-47160810-AAAG-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP6_Very_StrongBS2

The NM_001743.6(CALM2):c.422-9_422-7delCTT variant causes a splice region, 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, intron

Scores

Not classified

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.99

Publications

0 publications found

Variant links:

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 Gene-Disease associations (from GenCC):

long QT syndrome
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
long QT syndrome 15
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
catecholaminergic polymorphic ventricular tachycardia
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Genomics England PanelApp, ClinGen, G2P

CALM2 links:

ENSG00000273269 (HGNC:):

ENSG00000273269 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId 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	Effect	Exon rank	MANE	Protein	UniProt
CALM2	NM_001743.6 link	c.422-9_422-7delCTT	splice_region_variant, intron_variant	Intron 5 of 5	ENST00000272298.12	NP_001734.1	P0DP23P0DP24P0DP25B4DJ51
CALM2	NM_001305624.1 link	c.566-9_566-7delCTT	splice_region_variant, intron_variant	Intron 6 of 6		NP_001292553.1	P0DP24
CALM2	NM_001305625.2 link	c.314-9_314-7delCTT	splice_region_variant, intron_variant	Intron 5 of 5		NP_001292554.1	P0DP24Q96HY3
CALM2	NM_001305626.1 link	c.314-9_314-7delCTT	splice_region_variant, intron_variant	Intron 4 of 4		NP_001292555.1	P0DP24Q96HY3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CALM2	ENST00000272298.12 link	c.422-9_422-7delCTT		splice_region_variant, intron_variant	Intron 5 of 5	1	NM_001743.6	ENSP00000272298.7		P0DP24
ENSG00000273269	ENST00000422269.1 link	n.101-7797_101-7795delCTT		intron_variant	Intron 2 of 8	2		ENSP00000476793.1		V9GYI7

Frequencies

GnomAD3 genomes

AF:

0.000139

AC:

AN:

151190

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.0000442

AC:

AN:

158268

AF XY:

0.0000118

show subpopulations

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000675

AC:

AN:

1333250

Hom.:

AF XY:

0.0000650

AC XY:

AN XY:

661874

show subpopulations

African (AFR)

AF:

0.000135

AC:

AN:

29610

American (AMR)

AF:

0.00

AC:

AN:

31920

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23902

East Asian (EAS)

AF:

0.0000265

AC:

AN:

37714

South Asian (SAS)

AF:

0.0000139

AC:

AN:

72048

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49684

Middle Eastern (MID)

AF:

0.00118

AC:

AN:

4232

European-Non Finnish (NFE)

AF:

0.0000739

AC:

AN:

1028996

Other (OTH)

AF:

0.0000544

AC:

AN:

55144

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000139

AC:

AN:

151190

Hom.:

Cov.:

AF XY:

0.000122

AC XY:

AN XY:

73758

show subpopulations

African (AFR)

AF:

0.0000971

AC:

AN:

41176

American (AMR)

AF:

0.00

AC:

AN:

15080

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.000195

AC:

AN:

5140

South Asian (SAS)

AF:

0.00

AC:

AN:

4800

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

312

European-Non Finnish (NFE)

AF:

0.000236

AC:

AN:

67826

Other (OTH)

AF:

0.00

AC:

AN:

2066

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000253

Hom.:

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Long QT syndrome 1

Benign:1

Jan 07, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

May 19, 2022

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

See Variant Classification Assertion Criteria. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.0

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over