rs10823148

Variant names:

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.1884C>G(p.Phe628Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.483 in 1,613,842 control chromosomes in the GnomAD database, including 196,299 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.40 ( 13839 hom., cov: 31)

Exomes 𝑓: 0.49 ( 182460 hom. )

Consequence

MYPN
NM_032578.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.71

Publications

40 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:

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=3.222823E-4).

BP6

Variant 10-68166577-C-G is Benign according to our data. Variant chr10-68166577-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 31804.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.513 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYPN	NM_032578.4 link	c.1884C>G	p.Phe628Leu	missense_variant	Exon 10 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.1884C>G	p.Phe628Leu	missense_variant	Exon 10 of 20	1	NM_032578.4	ENSP00000351790.5		Q86TC9-1

Frequencies

GnomAD3 genomes

AF:

0.396

AC:

60141

AN:

151876

Hom.:

13846

Cov.:

show subpopulations

Gnomad AFR

AF:

0.167

Gnomad AMI

AF:

0.532

Gnomad AMR

AF:

0.434

Gnomad ASJ

AF:

0.314

Gnomad EAS

AF:

0.212

Gnomad SAS

AF:

0.436

Gnomad FIN

AF:

0.546

Gnomad MID

AF:

0.259

Gnomad NFE

AF:

0.518

Gnomad OTH

AF:

0.391

GnomAD2 exomes

AF:

0.440

AC:

110543

AN:

251344

AF XY:

0.447

show subpopulations

Gnomad AFR exome

AF:

0.157

Gnomad AMR exome

AF:

0.431

Gnomad ASJ exome

AF:

0.328

Gnomad EAS exome

AF:

0.195

Gnomad FIN exome

AF:

0.544

Gnomad NFE exome

AF:

0.513

Gnomad OTH exome

AF:

0.443

GnomAD4 exome

AF:

0.492

AC:

719955

AN:

1461848

Hom.:

182460

Cov.:

AF XY:

0.492

AC XY:

357766

AN XY:

727228

show subpopulations

African (AFR)

AF:

0.152

AC:

5080

AN:

33480

American (AMR)

AF:

0.429

AC:

19180

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.326

AC:

8509

AN:

26136

East Asian (EAS)

AF:

0.239

AC:

9500

AN:

39696

South Asian (SAS)

AF:

0.443

AC:

38198

AN:

86258

European-Finnish (FIN)

AF:

0.540

AC:

28863

AN:

53414

Middle Eastern (MID)

AF:

0.343

AC:

1977

AN:

5768

European-Non Finnish (NFE)

AF:

0.523

AC:

581566

AN:

1111980

Other (OTH)

AF:

0.448

AC:

27082

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

22610

45220

67830

90440

113050

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

16360

32720

49080

65440

81800

<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:

0.396

AC:

60150

AN:

151994

Hom.:

13839

Cov.:

AF XY:

0.396

AC XY:

29416

AN XY:

74304

show subpopulations

African (AFR)

AF:

0.167

AC:

6928

AN:

41480

American (AMR)

AF:

0.433

AC:

6612

AN:

15254

Ashkenazi Jewish (ASJ)

AF:

0.314

AC:

1089

AN:

3470

East Asian (EAS)

AF:

0.211

AC:

1092

AN:

5164

South Asian (SAS)

AF:

0.436

AC:

2099

AN:

4814

European-Finnish (FIN)

AF:

0.546

AC:

5771

AN:

10566

Middle Eastern (MID)

AF:

0.238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.518

AC:

35179

AN:

67928

Other (OTH)

AF:

0.391

AC:

825

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1675

3349

5024

6698

8373

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

556

1112

1668

2224

2780

<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:

0.475

Hom.:

13584

Bravo

AF:

0.372

TwinsUK

AF:

0.530

AC:

1966

ALSPAC

AF:

0.512

AC:

1973

ESP6500AA

AF:

0.174

AC:

768

ESP6500EA

AF:

0.510

AC:

4382

ExAC

AF:

0.438

AC:

53153

Asia WGS

AF:

0.298

AC:

1037

AN:

3478

EpiCase

AF:

0.503

EpiControl

AF:

0.493

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Nov 13, 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. -

Oct 29, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Phe628Leu in exon 11 of MYPN: This variant is not expected to have clinical si gnificance because it has been identified in 51% (4382/8600) of European America n chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.ed u/EVS/; dbSNP rs10823148). -

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

- -

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

Apr 04, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dilated cardiomyopathy 1KK

Benign:2

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

- -

MYPN-related myopathy

Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Jun 16, 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

Uncertain

0.55

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.49

CADD

Benign

(source)

DANN

Benign

0.65

DEOGEN2

Benign

0.020

.;.;.;T

Eigen

Benign

-0.28

Eigen_PC

Benign

-0.13

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.74

T;T;.;T

MetaRNN

Benign

0.00032

T;T;T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

0.83

L;.;L;.

PhyloP100

1.7

PrimateAI

Benign

0.44

PROVEAN

Benign

-0.33

N;N;N;.

REVEL

Benign

0.058

Sift

Benign

0.56

T;T;T;.

Sift4G

Benign

0.72

T;T;T;T

Polyphen

0.0010

B;B;B;.

Vest4

0.12

MutPred

0.27

Loss of sheet (P = 0.0181);.;Loss of sheet (P = 0.0181);.;

MPC

0.16

ClinPred

0.0097

GERP RS

4.3

Varity_R

0.097

gMVP

0.26

Mutation Taster

=83/17

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