Genetic Variant CALM3:c.-157T>A (chr19-46601278-T-A) – ACMG Classification: Benign (-18 pts)

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBA1

The NM_001329921.1(CALM3):c.-106+102T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.188 in 544,608 control chromosomes in the GnomAD database, including 11,146 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.16 ( 2483 hom., cov: 32)

Exomes 𝑓: 0.20 ( 8663 hom. )

Consequence

CALM3
NM_001329921.1 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.301

Publications

9 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: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
catecholaminergic polymorphic ventricular tachycardia
Inheritance: AD Classification: MODERATE Submitted by: G2P, ClinGen

CALM3 links:

ENSG00000291145 (HGNC:):

ENSG00000291145 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.29).

BP6

Variant 19-46601278-T-A is Benign according to our data. Variant chr19-46601278-T-A is described in ClinVar as Benign. ClinVar VariationId is 1167461.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.365 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001329921.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CALM3	NM_001329921.1		c.-106+102T>A	intron	N/A	NP_001316850.1	Q96HY3
CALM3	NM_005184.4	MANE Select	c.-157T>A	upstream_gene	N/A	NP_005175.2	P0DP25
CALM3	NM_001329924.2		c.-263T>A	upstream_gene	N/A	NP_001316853.1

Ensembl Transcripts

Gene	Transcript	HGVSc	Effect	Exon Rank	Protein
CALM3	ENST00000866714.1	c.-157T>A	5_prime_UTR	Exon 1 of 6	ENSP00000536773.1
CALM3	ENST00000866717.1	c.-62T>A	5_prime_UTR	Exon 1 of 7	ENSP00000536776.1
CALM3	ENST00000866716.1	c.-157T>A	5_prime_UTR	Exon 1 of 6	ENSP00000536775.1

Frequencies

GnomAD3 genomes

AF:

0.161

AC:

23885

AN:

148300

Hom.:

2484

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0709

Gnomad AMI

AF:

0.248

Gnomad AMR

AF:

0.123

Gnomad ASJ

AF:

0.0911

Gnomad EAS

AF:

0.379

Gnomad SAS

AF:

0.143

Gnomad FIN

AF:

0.308

Gnomad MID

AF:

0.0487

Gnomad NFE

AF:

0.192

Gnomad OTH

AF:

0.139

GnomAD4 exome

AF:

0.198

AC:

78428

AN:

396200

Hom.:

8663

Cov.:

AF XY:

0.199

AC XY:

39581

AN XY:

198484

show subpopulations

African (AFR)

AF:

0.0593

AC:

451

AN:

7608

American (AMR)

AF:

0.117

AC:

343

AN:

2928

Ashkenazi Jewish (ASJ)

AF:

0.0901

AC:

443

AN:

4916

East Asian (EAS)

AF:

0.329

AC:

3330

AN:

10114

South Asian (SAS)

AF:

0.195

AC:

2527

AN:

12950

European-Finnish (FIN)

AF:

0.331

AC:

3255

AN:

9820

Middle Eastern (MID)

AF:

0.0655

AC:

AN:

1130

European-Non Finnish (NFE)

AF:

0.196

AC:

65007

AN:

331040

Other (OTH)

AF:

0.191

AC:

2998

AN:

15694

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.526

Heterozygous variant carriers

2850

5700

8549

11399

14249

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2270

4540

6810

9080

11350

<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:

0.161

AC:

23882

AN:

148408

Hom.:

2483

Cov.:

AF XY:

0.165

AC XY:

11974

AN XY:

72438

show subpopulations

African (AFR)

AF:

0.0708

AC:

2891

AN:

40852

American (AMR)

AF:

0.122

AC:

1833

AN:

14968

Ashkenazi Jewish (ASJ)

AF:

0.0911

AC:

311

AN:

3414

East Asian (EAS)

AF:

0.379

AC:

1924

AN:

5074

South Asian (SAS)

AF:

0.143

AC:

686

AN:

4784

European-Finnish (FIN)

AF:

0.308

AC:

2869

AN:

9314

Middle Eastern (MID)

AF:

0.0524

AC:

AN:

286

European-Non Finnish (NFE)

AF:

0.192

AC:

12847

AN:

66764

Other (OTH)

AF:

0.138

AC:

284

AN:

2058

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1009

2018

3026

4035

5044

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

258

516

774

1032

1290

<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:

0.163

Hom.:

282

Bravo

AF:

0.144

Asia WGS

AF:

0.245

AC:

825

AN:

3374

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Long QT syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.29

CADD

Benign

(source)

DANN

Benign

0.93

PhyloP100

0.30

PromoterAI

0.17

Neutral

(source)

Mutation Taster

=299/1

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

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over