Genetic Variant NM_005184.4:c.*728A>G (chr19-46609881-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The NM_005184.4(CALM3):c.*728A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.921 in 152,844 control chromosomes in the GnomAD database, including 64,862 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 0.92 ( 64572 hom., cov: 31)

Exomes 𝑓: 0.91 ( 290 hom. )

Consequence

CALM3
NM_005184.4 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.618

Publications

14 publications found

Variant links:

Genes affected

CALM3 (HGNC:1449): (calmodulin 3) This gene encodes a member of a family of proteins that binds calcium and functions as a enzymatic co-factor. Activity of this protein is important in the regulation of the cell cycle and cytokinesis. Multiple alternatively spliced transcript variants have been observed at this gene. [provided by RefSeq, Aug 2016]

CALM3 Gene-Disease associations (from GenCC):

familial long QT syndrome
Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
long QT syndrome
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
long QT syndrome 16
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
catecholaminergic polymorphic ventricular tachycardia
Inheritance: AD Classification: MODERATE Submitted by: ClinGen, G2P

CALM3 links:

ENSG00000269292 (HGNC:):

ENSG00000269292 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=-0.6).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.951 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CALM3	NM_005184.4 link	c.*728A>G		3_prime_UTR_variant	Exon 6 of 6	ENST00000291295.14	NP_005175.2	P0DP23P0DP24P0DP25B4DJ51Q9BRL5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CALM3	ENST00000291295.14 link	c.*728A>G		3_prime_UTR_variant	Exon 6 of 6	1	NM_005184.4	ENSP00000291295.8		P0DP25

Frequencies

GnomAD3 genomes

AF:

0.921

AC:

139986

AN:

152026

Hom.:

64513

Cov.:

show subpopulations

Gnomad AFR

AF:

0.957

Gnomad AMI

AF:

0.879

Gnomad AMR

AF:

0.934

Gnomad ASJ

AF:

0.934

Gnomad EAS

AF:

0.974

Gnomad SAS

AF:

0.960

Gnomad FIN

AF:

0.900

Gnomad MID

AF:

0.921

Gnomad NFE

AF:

0.892

Gnomad OTH

AF:

0.913

GnomAD4 exome

AF:

0.914

AC:

640

AN:

700

Hom.:

290

Cov.:

AF XY:

0.931

AC XY:

432

AN XY:

464

show subpopulations

African (AFR)

AF:

0.833

AC:

AN:

American (AMR)

AF:

1.00

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

1.00

AC:

AN:

East Asian (EAS)

AF:

1.00

AC:

AN:

South Asian (SAS)

AF:

0.955

AC:

AN:

European-Finnish (FIN)

AF:

0.907

AC:

401

AN:

442

Middle Eastern (MID)

AF:

1.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.921

AC:

186

AN:

202

Other (OTH)

AF:

0.929

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

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:

0.921

AC:

140104

AN:

152144

Hom.:

64572

Cov.:

AF XY:

0.923

AC XY:

68623

AN XY:

74380

show subpopulations

African (AFR)

AF:

0.957

AC:

39716

AN:

41504

American (AMR)

AF:

0.934

AC:

14279

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.934

AC:

3244

AN:

3472

East Asian (EAS)

AF:

0.974

AC:

5016

AN:

5150

South Asian (SAS)

AF:

0.960

AC:

4634

AN:

4826

European-Finnish (FIN)

AF:

0.900

AC:

9521

AN:

10582

Middle Eastern (MID)

AF:

0.918

AC:

270

AN:

294

European-Non Finnish (NFE)

AF:

0.892

AC:

60689

AN:

68010

Other (OTH)

AF:

0.914

AC:

1933

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

571

1142

1712

2283

2854

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

908

1816

2724

3632

4540

<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:

0.909

Hom.:

91992

Bravo

AF:

0.925

Asia WGS

AF:

0.977

AC:

3396

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.60

CADD

Benign

2.9

(source)

DANN

Benign

0.78

PhyloP100

-0.62

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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