rs10997975

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.2072G>A(p.Ser691Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.465 in 1,613,462 control chromosomes in the GnomAD database, including 179,292 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S691T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.39 ( 12983 hom., cov: 31)

Exomes 𝑓: 0.47 ( 166309 hom. )

Consequence

MYPN
NM_032578.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12O:1

Conservation

PhyloP100: 0.447

Publications

48 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=5.6671222E-5).

BP6

Variant 10-68174164-G-A is Benign according to our data. Variant chr10-68174164-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 31797.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.485 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYPN	NM_032578.4 link	c.2072G>A	p.Ser691Asn	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.2072G>A	p.Ser691Asn	missense_variant	Exon 11 of 20	1	NM_032578.4	ENSP00000351790.5		Q86TC9-1

Frequencies

GnomAD3 genomes

AF:

0.394

AC:

59819

AN:

151722

Hom.:

12985

Cov.:

show subpopulations

Gnomad AFR

AF:

0.212

Gnomad AMI

AF:

0.423

Gnomad AMR

AF:

0.419

Gnomad ASJ

AF:

0.319

Gnomad EAS

AF:

0.263

Gnomad SAS

AF:

0.430

Gnomad FIN

AF:

0.531

Gnomad MID

AF:

0.253

Gnomad NFE

AF:

0.490

Gnomad OTH

AF:

0.392

GnomAD2 exomes

AF:

0.431

AC:

108356

AN:

251472

AF XY:

0.436

show subpopulations

Gnomad AFR exome

AF:

0.205

Gnomad AMR exome

AF:

0.419

Gnomad ASJ exome

AF:

0.329

Gnomad EAS exome

AF:

0.247

Gnomad FIN exome

AF:

0.530

Gnomad NFE exome

AF:

0.487

Gnomad OTH exome

AF:

0.432

GnomAD4 exome

AF:

0.472

AC:

690328

AN:

1461622

Hom.:

166309

Cov.:

AF XY:

0.472

AC XY:

343250

AN XY:

727130

show subpopulations

African (AFR)

AF:

0.201

AC:

6728

AN:

33474

American (AMR)

AF:

0.417

AC:

18666

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.326

AC:

8523

AN:

26134

East Asian (EAS)

AF:

0.313

AC:

12408

AN:

39700

South Asian (SAS)

AF:

0.435

AC:

37500

AN:

86252

European-Finnish (FIN)

AF:

0.526

AC:

28098

AN:

53416

Middle Eastern (MID)

AF:

0.356

AC:

2056

AN:

5768

European-Non Finnish (NFE)

AF:

0.495

AC:

550034

AN:

1111768

Other (OTH)

AF:

0.436

AC:

26315

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

22899

45798

68696

91595

114494

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

15836

31672

47508

63344

79180

<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:

0.394

AC:

59850

AN:

151840

Hom.:

12983

Cov.:

AF XY:

0.395

AC XY:

29270

AN XY:

74192

show subpopulations

African (AFR)

AF:

0.213

AC:

8803

AN:

41414

American (AMR)

AF:

0.419

AC:

6388

AN:

15248

Ashkenazi Jewish (ASJ)

AF:

0.319

AC:

1104

AN:

3466

East Asian (EAS)

AF:

0.263

AC:

1353

AN:

5154

South Asian (SAS)

AF:

0.431

AC:

2069

AN:

4804

European-Finnish (FIN)

AF:

0.531

AC:

5572

AN:

10496

Middle Eastern (MID)

AF:

0.231

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.490

AC:

33282

AN:

67946

Other (OTH)

AF:

0.392

AC:

825

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1763

3526

5288

7051

8814

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

566

1132

1698

2264

2830

<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:

0.451

Hom.:

71844

Bravo

AF:

0.372

TwinsUK

AF:

0.497

AC:

1844

ALSPAC

AF:

0.485

AC:

1869

ESP6500AA

AF:

0.222

AC:

976

ESP6500EA

AF:

0.480

AC:

4128

ExAC

AF:

0.431

AC:

52294

Asia WGS

AF:

0.322

AC:

1121

AN:

3478

EpiCase

AF:

0.478

EpiControl

AF:

0.469

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

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.Ser691Asn in exon 12 of MYPN: This variant is not expected to have clinical si gnificance because it has been identified in 48% (4128/8600) of European America n chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.ed u/EVS/; dbSNP rs10997975). -

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

- -

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

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

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Dilated cardiomyopathy 1KK

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 05, 2021

Genome-Nilou Lab

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

Benign

0.10

BayesDel_addAF

Benign

-0.75

BayesDel_noAF

Benign

-0.70

CADD

Benign

(source)

DANN

Benign

0.18

DEOGEN2

Benign

0.018

.;.;.;T

Eigen

Benign

-0.98

Eigen_PC

Benign

-0.80

FATHMM_MKL

Benign

0.061

LIST_S2

Benign

0.13

T;T;.;T

MetaRNN

Benign

0.000057

T;T;T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

-1.8

N;.;N;.

PhyloP100

0.45

PrimateAI

Benign

0.35

PROVEAN

Benign

0.46

N;N;N;.

REVEL

Benign

0.042

Sift

Benign

1.0

T;T;T;.

Sift4G

Benign

0.59

T;T;T;T

Polyphen

0.0

B;B;B;.

Vest4

0.067

MPC

0.12

ClinPred

0.0019

GERP RS

3.2

Varity_R

0.037

gMVP

0.061

Mutation Taster

=100/0

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