Genetic Variant CALM2:c.421+75C>G (chr2-47161648-G-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

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

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.603

Publications

1 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: G2P, Genomics England PanelApp, ClinGen

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 -20 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 VariationId is 1214286.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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 the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High AC in GnomAd4 at 1858 AD gene.

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.421+75C>G	intron	N/A	NP_001734.1	P0DP24
CALM2	NM_001305624.1		c.565+75C>G	intron	N/A	NP_001292553.1	P0DP24
CALM2	NM_001305625.2		c.313+75C>G	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.421+75C>G	intron	N/A	ENSP00000272298.7	P0DP24
ENSG00000273269	ENST00000422269.1	TSL:2	n.101-8632C>G	intron	N/A	ENSP00000476793.1	V9GYI7
CALM2	ENST00000460218.5	TSL:1	n.3861+75C>G	intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.0122

AC:

1860

AN:

152070

Hom.:

Cov.:

show subpopulations

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

show subpopulations

African (AFR)

AF:

0.00238

AC:

AN:

26910

American (AMR)

AF:

0.00809

AC:

239

AN:

29528

Ashkenazi Jewish (ASJ)

AF:

0.00535

AC:

110

AN:

20562

East Asian (EAS)

AF:

0.00

AC:

AN:

35960

South Asian (SAS)

AF:

0.0101

AC:

678

AN:

66846

European-Finnish (FIN)

AF:

0.0328

AC:

1641

AN:

50056

Middle Eastern (MID)

AF:

0.0211

AC:

AN:

3552

European-Non Finnish (NFE)

AF:

0.0168

AC:

15902

AN:

947660

Other (OTH)

AF:

0.0150

AC:

772

AN:

51592

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

897

1795

2692

3590

4487

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

582

1164

1746

2328

2910

<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:

0.0122

AC:

1858

AN:

152188

Hom.:

Cov.:

AF XY:

0.0122

AC XY:

907

AN XY:

74382

show subpopulations

African (AFR)

AF:

0.00337

AC:

140

AN:

41522

American (AMR)

AF:

0.00791

AC:

121

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00778

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00788

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.0352

AC:

372

AN:

10582

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0166

AC:

1128

AN:

68002

Other (OTH)

AF:

0.0123

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

188

281

375

469

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

<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:

0.00526

Hom.:

Bravo

AF:

0.0102

Asia WGS

AF:

0.00289

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

CADD

Benign

0.48

(source)

DANN

Benign

0.38

PhyloP100

-0.60

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism

(source)

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over