Genetic Variant MYPN:p.Ala721Ala (chr10-68174255-C-A) – ACMG Classification: Benign (-19 pts)

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_032578.4(MYPN):c.2163C>A(p.Ala721Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0185 in 1,613,986 control chromosomes in the GnomAD database, including 761 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.041 ( 303 hom., cov: 31)

Exomes 𝑓: 0.016 ( 458 hom. )

Consequence

MYPN
NM_032578.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10O:1

Conservation

PhyloP100: 0.687

Publications

4 publications found

Variant links:

Genes affected

MYPN (HGNC:23246): (myopalladin) Striated muscle in vertebrates comprises large proteins which must be organized properly to contract efficiently. Z-lines in striated muscle are a sign of this organization, representing the ends of actin thin filaments, titin, nebulin or nebulette and accessory proteins required for structure and function. This gene encodes a protein which interacts with nebulin in skeletal muscle or nebulette in cardiac muscle and alpha-actinin. In addition, this gene product can interact with a protein with the I-band indicating it has a regulatory as well as structural function. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2011]

MYPN Gene-Disease associations (from GenCC):

MYPN-related myopathy
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)
cap myopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
childhood-onset nemaline myopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
familial isolated dilated cardiomyopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
familial isolated restrictive cardiomyopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
dilated cardiomyopathy
Inheritance: AD Classification: LIMITED Submitted by: ClinGen
dilated cardiomyopathy 1KK
Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
hypertrophic cardiomyopathy
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

MYPN links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.28).

BP6

Variant 10-68174255-C-A is Benign according to our data. Variant chr10-68174255-C-A is described in ClinVar as Benign. ClinVar VariationId is 31806.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.687 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.107 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032578.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MYPN	NM_032578.4	MANE Select	c.2163C>A	p.Ala721Ala	synonymous	Exon 11 of 20	NP_115967.2	Q86TC9-1
MYPN	NM_001256267.2		c.2163C>A	p.Ala721Ala	synonymous	Exon 12 of 21	NP_001243196.1	Q86TC9-1
MYPN	NM_001256268.2		c.1281C>A	p.Ala427Ala	synonymous	Exon 15 of 24	NP_001243197.1	A0A087WX60

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MYPN	ENST00000358913.10	TSL:1 MANE Select	c.2163C>A	p.Ala721Ala	synonymous	Exon 11 of 20	ENSP00000351790.5	Q86TC9-1
MYPN	ENST00000540630.6	TSL:1	c.2217C>A	p.Ala739Ala	synonymous	Exon 11 of 20	ENSP00000441668.3	A0A8J9ASZ5
MYPN	ENST00000613327.5	TSL:1	c.2163C>A	p.Ala721Ala	synonymous	Exon 12 of 21	ENSP00000480757.2	Q86TC9-1

Frequencies

GnomAD3 genomes

AF:

0.0403

AC:

6132

AN:

151982

Hom.:

299

Cov.:

show subpopulations

Gnomad AFR

AF:

0.109

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0193

Gnomad ASJ

AF:

0.0188

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0261

Gnomad FIN

AF:

0.0112

Gnomad MID

AF:

0.0411

Gnomad NFE

AF:

0.0139

Gnomad OTH

AF:

0.0354

GnomAD2 exomes

AF:

0.0217

AC:

5445

AN:

251444

AF XY:

0.0212

show subpopulations

Gnomad AFR exome

AF:

0.113

Gnomad AMR exome

AF:

0.0125

Gnomad ASJ exome

AF:

0.0189

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.0111

Gnomad NFE exome

AF:

0.0142

Gnomad OTH exome

AF:

0.0200

GnomAD4 exome

AF:

0.0163

AC:

23776

AN:

1461886

Hom.:

458

Cov.:

AF XY:

0.0167

AC XY:

12127

AN XY:

727246

show subpopulations

African (AFR)

AF:

0.118

AC:

3949

AN:

33480

American (AMR)

AF:

0.0135

AC:

602

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0182

AC:

476

AN:

26136

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39700

South Asian (SAS)

AF:

0.0332

AC:

2867

AN:

86258

European-Finnish (FIN)

AF:

0.0115

AC:

612

AN:

53418

Middle Eastern (MID)

AF:

0.0354

AC:

204

AN:

5768

European-Non Finnish (NFE)

AF:

0.0123

AC:

13720

AN:

1112006

Other (OTH)

AF:

0.0222

AC:

1343

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

1651

3303

4954

6606

8257

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

540

1080

1620

2160

2700

<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:

0.0405

AC:

6162

AN:

152100

Hom.:

303

Cov.:

AF XY:

0.0396

AC XY:

2944

AN XY:

74366

show subpopulations

African (AFR)

AF:

0.109

AC:

4525

AN:

41444

American (AMR)

AF:

0.0192

AC:

294

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.0188

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.0263

AC:

127

AN:

4824

European-Finnish (FIN)

AF:

0.0112

AC:

119

AN:

10602

Middle Eastern (MID)

AF:

0.0374

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0139

AC:

947

AN:

67992

Other (OTH)

AF:

0.0350

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

272

544

815

1087

1359

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

124

186

248

310

<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:

0.0290

Hom.:

Bravo

AF:

0.0445

Asia WGS

AF:

0.0170

AC:

AN:

3478

EpiCase

AF:

0.0172

EpiControl

AF:

0.0146

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (7)

Cardiovascular phenotype (1)

Dilated cardiomyopathy 1KK (1)

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.28

CADD

Benign

9.6

(source)

DANN

Benign

0.78

PhyloP100

0.69

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over