Genetic Variant CMYA5:p.Ala1333Val (chr5-79732763-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The NM_153610.5(CMYA5):c.3998C>T(p.Ala1333Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0872 in 1,613,406 control chromosomes in the GnomAD database, including 10,823 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.12 ( 1859 hom., cov: 33)

Exomes 𝑓: 0.083 ( 8964 hom. )

Consequence

CMYA5
NM_153610.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.876

Publications

15 publications found

Variant links:

Genes affected

CMYA5 (HGNC:14305): (cardiomyopathy associated 5) Predicted to enable identical protein binding activity. Predicted to act upstream of or within negative regulation of calcineurin-NFAT signaling cascade; negative regulation of phosphoprotein phosphatase activity; and regulation of skeletal muscle adaptation. Located in cytosol; nuclear speck; and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

CMYA5 links:

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ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.001995653).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.389 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CMYA5	NM_153610.5 link	c.3998C>T	p.Ala1333Val	missense_variant	Exon 2 of 13	ENST00000446378.3	NP_705838.3	Q8N3K9
CMYA5	XM_047416911.1 link	c.3998C>T	p.Ala1333Val	missense_variant	Exon 2 of 6		XP_047272867.1
CMYA5	XR_001742036.3 link	n.4070C>T		non_coding_transcript_exon_variant	Exon 2 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CMYA5	ENST00000446378.3 link	c.3998C>T	p.Ala1333Val	missense_variant	Exon 2 of 13	5	NM_153610.5	ENSP00000394770.2		Q8N3K9

Frequencies

GnomAD3 genomes

AF:

0.124

AC:

18813

AN:

152074

Hom.:

1843

Cov.:

show subpopulations

Gnomad AFR

AF:

0.230

Gnomad AMI

AF:

0.00877

Gnomad AMR

AF:

0.0551

Gnomad ASJ

AF:

0.0568

Gnomad EAS

AF:

0.402

Gnomad SAS

AF:

0.0909

Gnomad FIN

AF:

0.0978

Gnomad MID

AF:

0.0316

Gnomad NFE

AF:

0.0661

Gnomad OTH

AF:

0.0932

GnomAD2 exomes

AF:

0.103

AC:

25526

AN:

247654

AF XY:

0.0986

show subpopulations

Gnomad AFR exome

AF:

0.232

Gnomad AMR exome

AF:

0.0357

Gnomad ASJ exome

AF:

0.0521

Gnomad EAS exome

AF:

0.408

Gnomad FIN exome

AF:

0.0989

Gnomad NFE exome

AF:

0.0664

Gnomad OTH exome

AF:

0.0761

GnomAD4 exome

AF:

0.0833

AC:

121770

AN:

1461214

Hom.:

8964

Cov.:

AF XY:

0.0828

AC XY:

60162

AN XY:

726876

show subpopulations

African (AFR)

AF:

0.240

AC:

8030

AN:

33456

American (AMR)

AF:

0.0382

AC:

1705

AN:

44644

Ashkenazi Jewish (ASJ)

AF:

0.0550

AC:

1436

AN:

26126

East Asian (EAS)

AF:

0.465

AC:

18439

AN:

39666

South Asian (SAS)

AF:

0.0928

AC:

7999

AN:

86210

European-Finnish (FIN)

AF:

0.0985

AC:

5259

AN:

53364

Middle Eastern (MID)

AF:

0.0361

AC:

208

AN:

5764

European-Non Finnish (NFE)

AF:

0.0658

AC:

73200

AN:

1111624

Other (OTH)

AF:

0.0910

AC:

5494

AN:

60360

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

6195

12391

18586

24782

30977

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3024

6048

9072

12096

15120

<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:

0.124

AC:

18874

AN:

152192

Hom.:

1859

Cov.:

AF XY:

0.127

AC XY:

9445

AN XY:

74388

show subpopulations

African (AFR)

AF:

0.231

AC:

9580

AN:

41504

American (AMR)

AF:

0.0549

AC:

839

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0568

AC:

197

AN:

3468

East Asian (EAS)

AF:

0.403

AC:

2078

AN:

5156

South Asian (SAS)

AF:

0.0910

AC:

439

AN:

4826

European-Finnish (FIN)

AF:

0.0978

AC:

1037

AN:

10602

Middle Eastern (MID)

AF:

0.0306

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0660

AC:

4492

AN:

68022

Other (OTH)

AF:

0.0922

AC:

195

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

795

1590

2384

3179

3974

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

208

416

624

832

1040

<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:

0.0846

Hom.:

2961

Bravo

AF:

0.127

TwinsUK

AF:

0.0693

AC:

257

ALSPAC

AF:

0.0654

AC:

252

ESP6500AA

AF:

0.224

AC:

845

ESP6500EA

AF:

0.0659

AC:

541

ExAC

AF:

0.107

AC:

12890

Asia WGS

AF:

0.237

AC:

825

AN:

3478

EpiCase

AF:

0.0609

EpiControl

AF:

0.0560

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.80

BayesDel_noAF

Benign

-0.77

CADD

Benign

2.1

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.020

Eigen

Benign

-0.74

Eigen_PC

Benign

-0.68

FATHMM_MKL

Benign

0.029

LIST_S2

Benign

0.57

MetaRNN

Benign

0.0020

MetaSVM

Benign

-0.91

MutationAssessor

Benign

0.20

PhyloP100

-0.88

PrimateAI

Benign

0.23

PROVEAN

Benign

-0.66

REVEL

Benign

0.047

Sift

Benign

0.38

Sift4G

Benign

0.62

Polyphen

0.057

Vest4

0.016

MPC

0.055

ClinPred

0.0010

GERP RS

1.3

Varity_R

0.029

gMVP

0.18

Mutation Taster

=98/2

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