10-68174501-C-G

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.2409C>G(p.Ser803Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.546 in 1,613,720 control chromosomes in the GnomAD database, including 243,329 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S803N) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.52 ( 20749 hom., cov: 31)

Exomes 𝑓: 0.55 ( 222580 hom. )

Consequence

MYPN
NM_032578.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -3.22

Publications

38 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=2.4887882E-5).

BP6

Variant 10-68174501-C-G is Benign according to our data. Variant chr10-68174501-C-G is described in ClinVar as Benign. ClinVar VariationId is 31808.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.554 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYPN	NM_032578.4 link	c.2409C>G	p.Ser803Arg	missense_variant	Exon 11 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.2409C>G	p.Ser803Arg	missense_variant	Exon 11 of 20	1	NM_032578.4	ENSP00000351790.5

Frequencies

GnomAD3 genomes

AF:

0.518

AC:

78601

AN:

151766

Hom.:

20728

Cov.:

show subpopulations

Gnomad AFR

AF:

0.458

Gnomad AMI

AF:

0.411

Gnomad AMR

AF:

0.502

Gnomad ASJ

AF:

0.423

Gnomad EAS

AF:

0.368

Gnomad SAS

AF:

0.512

Gnomad FIN

AF:

0.634

Gnomad MID

AF:

0.383

Gnomad NFE

AF:

0.558

Gnomad OTH

AF:

0.523

GnomAD2 exomes

AF:

0.519

AC:

130288

AN:

251198

AF XY:

0.522

show subpopulations

Gnomad AFR exome

AF:

0.460

Gnomad AMR exome

AF:

0.463

Gnomad ASJ exome

AF:

0.430

Gnomad EAS exome

AF:

0.367

Gnomad FIN exome

AF:

0.631

Gnomad NFE exome

AF:

0.557

Gnomad OTH exome

AF:

0.512

GnomAD4 exome

AF:

0.549

AC:

802859

AN:

1461836

Hom.:

222580

Cov.:

AF XY:

0.549

AC XY:

399092

AN XY:

727222

show subpopulations

African (AFR)

AF:

0.455

AC:

15233

AN:

33480

American (AMR)

AF:

0.468

AC:

20928

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.429

AC:

11212

AN:

26136

East Asian (EAS)

AF:

0.349

AC:

13845

AN:

39694

South Asian (SAS)

AF:

0.513

AC:

44243

AN:

86256

European-Finnish (FIN)

AF:

0.622

AC:

33203

AN:

53412

Middle Eastern (MID)

AF:

0.462

AC:

2662

AN:

5766

European-Non Finnish (NFE)

AF:

0.566

AC:

629498

AN:

1111972

Other (OTH)

AF:

0.530

AC:

32035

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

24211

48422

72634

96845

121056

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

17460

34920

52380

69840

87300

<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:

0.518

AC:

78668

AN:

151884

Hom.:

20749

Cov.:

AF XY:

0.518

AC XY:

38447

AN XY:

74230

show subpopulations

African (AFR)

AF:

0.458

AC:

18979

AN:

41396

American (AMR)

AF:

0.502

AC:

7657

AN:

15258

Ashkenazi Jewish (ASJ)

AF:

0.423

AC:

1468

AN:

3470

East Asian (EAS)

AF:

0.368

AC:

1900

AN:

5168

South Asian (SAS)

AF:

0.513

AC:

2470

AN:

4816

European-Finnish (FIN)

AF:

0.634

AC:

6682

AN:

10540

Middle Eastern (MID)

AF:

0.378

AC:

111

AN:

294

European-Non Finnish (NFE)

AF:

0.558

AC:

37924

AN:

67926

Other (OTH)

AF:

0.524

AC:

1102

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1880

3760

5641

7521

9401

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

694

1388

2082

2776

3470

<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:

0.449

Hom.:

2259

Bravo

AF:

0.502

TwinsUK

AF:

0.559

AC:

2072

ALSPAC

AF:

0.564

AC:

2174

ESP6500AA

AF:

0.468

AC:

2064

ESP6500EA

AF:

0.551

AC:

4738

ExAC

AF:

0.520

AC:

63155

Asia WGS

AF:

0.432

AC:

1505

AN:

3478

EpiCase

AF:

0.551

EpiControl

AF:

0.541

ClinVar

Significance: Benign

Submissions summary: Benign:10Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Nov 20, 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.Ser803Arg in exon 12 of MYPN: This variant is not expected to have clinical si gnificance because it has been identified in 55% (4738/8600) of European America n chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.ed u/EVS/; dbSNP rs3814182). -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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: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

- -

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 12, 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

Pathogenic

0.57

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.39

CADD

Benign

1.2

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.032

.;.;.;T

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.22

LIST_S2

Benign

0.85

T;T;.;T

MetaRNN

Benign

0.000025

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.1

M;.;M;.

PhyloP100

-3.2

PrimateAI

Benign

0.39

PROVEAN

Benign

-0.42

N;N;N;.

REVEL

Benign

0.17

Sift

Uncertain

0.020

D;D;D;.

Sift4G

Benign

0.34

T;T;T;T

Polyphen

0.66

P;P;P;.

Vest4

0.38

MutPred

0.20

Loss of glycosylation at S803 (P = 0.0377);.;Loss of glycosylation at S803 (P = 0.0377);.;

MPC

0.39

ClinPred

0.039

GERP RS

-9.6

Varity_R

0.32

gMVP

0.31

Mutation Taster

=85/15

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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