chr2-47160816-G-A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_StrongBP6_Moderate

The NM_001743.6(CALM2):c.422-12C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.000050 ( 0 hom., cov: 16)

Exomes 𝑓: 0.000028 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CALM2
NM_001743.6 intron

Scores

Splicing: ADA: 0.000008543

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.61

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: G2P, Labcorp Genetics (formerly Invitae)
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: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.61).

BP6

Variant 2-47160816-G-A is Benign according to our data. Variant chr2-47160816-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 2188743.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001743.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CALM2	NM_001743.6	MANE Select	c.422-12C>T	intron	N/A	NP_001734.1	P0DP24
CALM2	NM_001305624.1		c.566-12C>T	intron	N/A	NP_001292553.1	P0DP24
CALM2	NM_001305625.2		c.314-12C>T	intron	N/A	NP_001292554.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CALM2	ENST00000272298.12	TSL:1 MANE Select	c.422-12C>T	intron	N/A	ENSP00000272298.7	P0DP24
ENSG00000273269	ENST00000422269.1	TSL:2	n.101-7800C>T	intron	N/A	ENSP00000476793.1	V9GYI7
CALM2	ENST00000460218.5	TSL:1	n.3862-12C>T	intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.0000496

AC:

AN:

60542

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000758

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000181

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000330

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00

AC:

AN:

95328

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000281

AC:

AN:

854886

Hom.:

Cov.:

AF XY:

0.0000239

AC XY:

AN XY:

418120

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

16200

American (AMR)

AF:

0.00

AC:

AN:

17082

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

16392

East Asian (EAS)

AF:

0.000485

AC:

AN:

24764

South Asian (SAS)

AF:

0.000111

AC:

AN:

27122

European-Finnish (FIN)

AF:

0.0000291

AC:

AN:

34402

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2470

European-Non Finnish (NFE)

AF:

0.0000117

AC:

AN:

682088

Other (OTH)

AF:

0.00

AC:

AN:

34366

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000000900047), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.348

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

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000495

AC:

AN:

60562

Hom.:

Cov.:

AF XY:

0.0000347

AC XY:

AN XY:

28856

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000755

AC:

AN:

13250

American (AMR)

AF:

0.000181

AC:

AN:

5516

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

1640

East Asian (EAS)

AF:

0.00

AC:

AN:

2644

South Asian (SAS)

AF:

0.00

AC:

AN:

2338

European-Finnish (FIN)

AF:

0.00

AC:

AN:

3640

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0000330

AC:

AN:

30326

Other (OTH)

AF:

0.00

AC:

AN:

800

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0662318), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.392

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Long QT syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.61

CADD

Benign

(source)

DANN

Benign

0.33

PhyloP100

1.6

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0000085

dbscSNV1_RF

Benign

0.0020

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over