rs11596653

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_032578.4(MYPN):c.1178T>C(p.Val393Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0316 in 1,613,918 control chromosomes in the GnomAD database, including 4,645 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.10 ( 2326 hom., cov: 32)

Exomes 𝑓: 0.024 ( 2319 hom. )

Consequence

MYPN
NM_032578.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7O:1

Conservation

PhyloP100: 0.416

Publications

14 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: Labcorp Genetics (formerly Invitae), ClinGen
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: PanelApp Australia, Labcorp Genetics (formerly Invitae)
hypertrophic cardiomyopathy
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

MYPN links:

LOC107984240 (HGNC:):

LOC107984240 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 (MetaRNN=0.0033382177).

BP6

Variant 10-68148400-T-C is Benign according to our data. Variant chr10-68148400-T-C is described in ClinVar as Benign. ClinVar VariationId is 31793.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.321 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYPN	NM_032578.4 link	c.1178T>C	p.Val393Ala	missense_variant	Exon 5 of 20	ENST00000358913.10	NP_115967.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYPN	ENST00000358913.10 link	c.1178T>C	p.Val393Ala	missense_variant	Exon 5 of 20	1	NM_032578.4	ENSP00000351790.5		Q86TC9-1

Frequencies

GnomAD3 genomes

AF:

0.104

AC:

15775

AN:

152070

Hom.:

2315

Cov.:

show subpopulations

Gnomad AFR

AF:

0.326

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0467

Gnomad ASJ

AF:

0.00951

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0274

Gnomad FIN

AF:

0.0140

Gnomad MID

AF:

0.0665

Gnomad NFE

AF:

0.0158

Gnomad OTH

AF:

0.0894

GnomAD2 exomes

AF:

0.0390

AC:

9797

AN:

251430

AF XY:

0.0342

show subpopulations

Gnomad AFR exome

AF:

0.333

Gnomad AMR exome

AF:

0.0264

Gnomad ASJ exome

AF:

0.00963

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.0127

Gnomad NFE exome

AF:

0.0159

Gnomad OTH exome

AF:

0.0316

GnomAD4 exome

AF:

0.0240

AC:

35104

AN:

1461730

Hom.:

2319

Cov.:

AF XY:

0.0237

AC XY:

17240

AN XY:

727166

show subpopulations

African (AFR)

AF:

0.336

AC:

11234

AN:

33456

American (AMR)

AF:

0.0283

AC:

1267

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00853

AC:

223

AN:

26134

East Asian (EAS)

AF:

0.000101

AC:

AN:

39700

South Asian (SAS)

AF:

0.0365

AC:

3148

AN:

86256

European-Finnish (FIN)

AF:

0.0128

AC:

684

AN:

53416

Middle Eastern (MID)

AF:

0.0569

AC:

328

AN:

5764

European-Non Finnish (NFE)

AF:

0.0142

AC:

15814

AN:

1111890

Other (OTH)

AF:

0.0398

AC:

2402

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

1667

3333

5000

6666

8333

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

724

1448

2172

2896

3620

<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:

0.104

AC:

15823

AN:

152188

Hom.:

2326

Cov.:

AF XY:

0.101

AC XY:

7481

AN XY:

74422

show subpopulations

African (AFR)

AF:

0.326

AC:

13514

AN:

41464

American (AMR)

AF:

0.0466

AC:

713

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00951

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.0276

AC:

133

AN:

4822

European-Finnish (FIN)

AF:

0.0140

AC:

149

AN:

10620

Middle Eastern (MID)

AF:

0.0680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0158

AC:

1074

AN:

68014

Other (OTH)

AF:

0.0885

AC:

187

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

584

1168

1753

2337

2921

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

146

292

438

584

730

<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:

0.0462

Hom.:

2285

Bravo

AF:

0.116

TwinsUK

AF:

0.0138

AC:

ALSPAC

AF:

0.0140

AC:

ESP6500AA

AF:

0.332

AC:

1464

ESP6500EA

AF:

0.0147

AC:

126

ExAC

AF:

0.0452

AC:

5491

Asia WGS

AF:

0.0360

AC:

125

AN:

3478

EpiCase

AF:

0.0183

EpiControl

AF:

0.0164

ClinVar

Significance: Benign

Submissions summary: Benign:7Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Dec 10, 2013

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

May 13, 2016

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Val393Ala in exon 6 of MYPN: This variant is not expected to have clinical sig nificance because it has been identified in 33.2% (1464/4406) of African America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs11596653). -

not provided

Benign:1Other:1

Apr 27, 2012

Leiden Muscular Dystrophy (MYPN)

Significance:not provided

Review Status:no classification provided

Collection Method:curation

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Dilated cardiomyopathy 1KK

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Jun 19, 2015

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.72

BayesDel_noAF

Benign

-0.67

CADD

Benign

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.024

.;.;.;T;.

Eigen

Benign

-0.70

Eigen_PC

Benign

-0.48

FATHMM_MKL

Benign

0.046

LIST_S2

Benign

0.046

T;T;.;T;T

MetaRNN

Benign

0.0033

T;T;T;T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

-0.20

N;.;N;.;N

PhyloP100

0.42

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.090

N;N;N;.;N

REVEL

Benign

0.037

Sift

Benign

0.45

T;T;T;.;T

Sift4G

Benign

0.40

T;T;T;T;T

Polyphen

0.0

B;B;B;.;B

Vest4

0.049

MPC

0.16

ClinPred

0.0021

GERP RS

2.5

Varity_R

0.034

gMVP

0.16

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over