Genetic Variant CALM3:p.Ala103Ala (chr19-46608869-C-T) – ACMG Classification: Benign (-17 pts)

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS2

The NM_005184.4(CALM3):c.309C>T(p.Ala103Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000512 in 1,583,336 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000041 ( 0 hom. )

Consequence

CALM3
NM_005184.4 synonymous

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -4.43

Publications

1 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:

LOC124904729 (HGNC:):

LOC124904729 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -17 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.54).

BP6

Variant 19-46608869-C-T is Benign according to our data. Variant chr19-46608869-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 458196.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-4.43 with no splicing effect.

BS2

High AC in GnomAd4 at 22 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005184.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CALM3	NM_005184.4	MANE Select	c.309C>T	p.Ala103Ala	synonymous	Exon 5 of 6	NP_005175.2	P0DP25
CALM3	NM_001329922.1		c.309C>T	p.Ala103Ala	synonymous	Exon 5 of 6	NP_001316851.1	P0DP23
CALM3	NM_001329921.1		c.201C>T	p.Ala67Ala	synonymous	Exon 5 of 6	NP_001316850.1	Q96HY3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CALM3	ENST00000291295.14	TSL:1 MANE Select	c.309C>T	p.Ala103Ala	synonymous	Exon 5 of 6	ENSP00000291295.8	P0DP25
CALM3	ENST00000599839.5	TSL:1	c.201C>T	p.Ala67Ala	synonymous	Exon 6 of 7	ENSP00000471225.1	Q96HY3
CALM3	ENST00000866718.1		c.345C>T	p.Ala115Ala	synonymous	Exon 5 of 6	ENSP00000536777.1

Frequencies

GnomAD3 genomes

AF:

0.000145

AC:

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000410

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000578

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000628

AC:

AN:

222860

AF XY:

0.0000504

show subpopulations

Gnomad AFR exome

AF:

0.000251

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000225

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000394

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000412

AC:

AN:

1431052

Hom.:

Cov.:

AF XY:

0.0000479

AC XY:

AN XY:

709232

show subpopulations

African (AFR)

AF:

0.000153

AC:

AN:

32640

American (AMR)

AF:

0.0000246

AC:

AN:

40580

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23596

East Asian (EAS)

AF:

0.000228

AC:

AN:

39532

South Asian (SAS)

AF:

0.0000749

AC:

AN:

80142

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52174

Middle Eastern (MID)

AF:

0.000376

AC:

AN:

5326

European-Non Finnish (NFE)

AF:

0.0000301

AC:

AN:

1097968

Other (OTH)

AF:

0.0000508

AC:

AN:

59094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

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

AF:

0.000144

AC:

AN:

152284

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74456

show subpopulations

African (AFR)

AF:

0.000409

AC:

AN:

41558

American (AMR)

AF:

0.00

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000579

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000122

Hom.:

Bravo

AF:

0.000106

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

CALM3-related disorder (1)

Cardiovascular phenotype (1)

Long QT syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.54

CADD

Benign

4.3

(source)

DANN

Benign

0.70

PhyloP100

-4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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