Genetic Variant ENST00000553964.5:n.1540C>G (chr14-90399471-C-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The ENST00000553964.5(CALM1):n.1540C>G variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0936 in 152,792 control chromosomes in the GnomAD database, including 1,410 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.094 ( 1408 hom., cov: 33)

Exomes 𝑓: 0.082 ( 2 hom. )

Consequence

CALM1
ENST00000553964.5 non_coding_transcript_exon

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.310

Publications

0 publications found

Variant links:

Genes affected

CALM1 (HGNC:1442): (calmodulin 1) This gene encodes one of three calmodulin proteins which are members of the EF-hand calcium-binding protein family. Calcium-induced activation of calmodulin regulates and modulates the function of cardiac ion channels. Two pseudogenes have been identified on chromosome 7 and X. Multiple transcript variants encoding different isoforms have been found for this gene.A missense mutation in the CALM1 gene has been associated with ventricular tachycardia.[provided by RefSeq, May 2020]

CALM1 Gene-Disease associations (from GenCC):

long QT syndrome
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
long QT syndrome 14
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P
catecholaminergic polymorphic ventricular tachycardia 4
Inheritance: AD Classification: STRONG, MODERATE Submitted by: G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
catecholaminergic polymorphic ventricular tachycardia
Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: Orphanet, ClinGen

CALM1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.68).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.556 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
CALM1	NM_006888.6 link	c.4-594C>G	intron_variant	Intron 1 of 5	ENST00000356978.9	NP_008819.1	P0DP23P0DP24P0DP25B4DJ51
CALM1	NM_001363670.2 link	c.6+384C>G	intron_variant	Intron 1 of 5		NP_001350599.1
CALM1	NM_001363669.2 link	c.-105-594C>G	intron_variant	Intron 1 of 5		NP_001350598.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CALM1	ENST00000356978.9 link	c.4-594C>G		intron_variant	Intron 1 of 5	1	NM_006888.6	ENSP00000349467.4		P0DP23

Frequencies

GnomAD3 genomes

AF:

0.0937

AC:

14257

AN:

152140

Hom.:

1414

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0552

Gnomad AMI

AF:

0.254

Gnomad AMR

AF:

0.155

Gnomad ASJ

AF:

0.103

Gnomad EAS

AF:

0.574

Gnomad SAS

AF:

0.113

Gnomad FIN

AF:

0.0715

Gnomad MID

AF:

0.0443

Gnomad NFE

AF:

0.0666

Gnomad OTH

AF:

0.0908

GnomAD4 exome

AF:

0.0824

AC:

AN:

534

Hom.:

Cov.:

AF XY:

0.0756

AC XY:

AN XY:

410

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AF:

0.100

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.167

AC:

AN:

East Asian (EAS)

AF:

0.625

AC:

AN:

South Asian (SAS)

AF:

0.0843

AC:

AN:

356

European-Finnish (FIN)

AF:

0.00

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0486

AC:

AN:

144

Other (OTH)

AF:

0.00

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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:

0.0937

AC:

14259

AN:

152258

Hom.:

1408

Cov.:

AF XY:

0.0992

AC XY:

7386

AN XY:

74434

show subpopulations

African (AFR)

AF:

0.0551

AC:

2291

AN:

41542

American (AMR)

AF:

0.155

AC:

2367

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.103

AC:

358

AN:

3468

East Asian (EAS)

AF:

0.574

AC:

2969

AN:

5176

South Asian (SAS)

AF:

0.114

AC:

548

AN:

4828

European-Finnish (FIN)

AF:

0.0715

AC:

759

AN:

10616

Middle Eastern (MID)

AF:

0.0408

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0666

AC:

4531

AN:

68018

Other (OTH)

AF:

0.0913

AC:

193

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

615

1230

1844

2459

3074

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

156

312

468

624

780

<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:

0.0719

Hom.:

Bravo

AF:

0.101

Asia WGS

AF:

0.295

AC:

1024

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.68

CADD

Benign

7.6

(source)

DANN

Benign

0.67

PhyloP100

-0.31

PromoterAI

0.0067

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over