dbSNP rs201296349: CALM3:c.-14C>A (chr19-46601421-C-A) – 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_005184.4(CALM3):c.-14C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.015 in 1,504,984 control chromosomes in the GnomAD database, including 227 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.011 ( 17 hom., cov: 32)

Exomes 𝑓: 0.016 ( 210 hom. )

Consequence

CALM3
NM_005184.4 5_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.742

Publications

3 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.7).

BP6

Variant 19-46601421-C-A is Benign according to our data. Variant chr19-46601421-C-A is described in ClinVar as Benign. ClinVar VariationId is 386525.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 = 0.0107 (1630/152270) while in subpopulation NFE AF = 0.0169 (1151/67988). AF 95% confidence interval is 0.0161. There are 17 homozygotes in GnomAd4. There are 699 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 1630 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	Effect	Exon Rank	Protein	UniProt
CALM3	NM_005184.4	MANE Select	c.-14C>A	5_prime_UTR	Exon 1 of 6	NP_005175.2	P0DP25
CALM3	NM_001329924.2		c.-120C>A	5_prime_UTR	Exon 1 of 6	NP_001316853.1
CALM3	NM_001329925.2		c.-91C>A	5_prime_UTR	Exon 1 of 5	NP_001316854.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CALM3	ENST00000291295.14	TSL:1 MANE Select	c.-14C>A	5_prime_UTR	Exon 1 of 6	ENSP00000291295.8	P0DP25
CALM3	ENST00000866718.1		c.-14C>A	5_prime_UTR	Exon 1 of 6	ENSP00000536777.1
CALM3	ENST00000866714.1		c.-14C>A	5_prime_UTR	Exon 1 of 6	ENSP00000536773.1

Frequencies

GnomAD3 genomes

AF:

0.0107

AC:

1630

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00362

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00667

Gnomad ASJ

AF:

0.0334

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00352

Gnomad FIN

AF:

0.00566

Gnomad MID

AF:

0.0316

Gnomad NFE

AF:

0.0169

Gnomad OTH

AF:

0.0115

GnomAD2 exomes

AF:

0.0122

AC:

1238

AN:

101626

AF XY:

0.0120

show subpopulations

Gnomad AFR exome

AF:

0.00237

Gnomad AMR exome

AF:

0.00816

Gnomad ASJ exome

AF:

0.0346

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00374

Gnomad NFE exome

AF:

0.0177

Gnomad OTH exome

AF:

0.0167

GnomAD4 exome

AF:

0.0155

AC:

20996

AN:

1352714

Hom.:

210

Cov.:

AF XY:

0.0154

AC XY:

10295

AN XY:

667880

show subpopulations

African (AFR)

AF:

0.00265

AC:

AN:

27896

American (AMR)

AF:

0.00802

AC:

259

AN:

32282

Ashkenazi Jewish (ASJ)

AF:

0.0363

AC:

869

AN:

23966

East Asian (EAS)

AF:

0.00

AC:

AN:

30580

South Asian (SAS)

AF:

0.00587

AC:

452

AN:

77008

European-Finnish (FIN)

AF:

0.00568

AC:

225

AN:

39632

Middle Eastern (MID)

AF:

0.0285

AC:

135

AN:

4738

European-Non Finnish (NFE)

AF:

0.0171

AC:

18106

AN:

1060740

Other (OTH)

AF:

0.0157

AC:

876

AN:

55872

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

892

1784

2675

3567

4459

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

706

1412

2118

2824

3530

<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:

0.0107

AC:

1630

AN:

152270

Hom.:

Cov.:

AF XY:

0.00939

AC XY:

699

AN XY:

74452

show subpopulations

African (AFR)

AF:

0.00361

AC:

150

AN:

41586

American (AMR)

AF:

0.00673

AC:

103

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0334

AC:

116

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.00352

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00566

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.0340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0169

AC:

1151

AN:

67988

Other (OTH)

AF:

0.0109

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

166

248

331

414

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:

0.0169

Hom.:

Bravo

AF:

0.0111

Asia WGS

AF:

0.00231

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.70

CADD

Benign

(source)

DANN

Benign

0.77

PhyloP100

0.74

PromoterAI

0.016

Neutral

(source)

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.0

Mutation Taster

=300/0

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