rs7916821

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.2120G>A(p.Ser707Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.462 in 1,613,710 control chromosomes in the GnomAD database, including 177,811 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S707G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.39 ( 12850 hom., cov: 30)

Exomes 𝑓: 0.47 ( 164961 hom. )

Consequence

MYPN
NM_032578.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.843

Publications

50 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=0.0013567209).

BP6

Variant 10-68174212-G-A is Benign according to our data. Variant chr10-68174212-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 31798.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.2120G>A	p.Ser707Asn	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.2120G>A	p.Ser707Asn	missense_variant	Exon 11 of 20	1	NM_032578.4	ENSP00000351790.5		Q86TC9-1

Frequencies

GnomAD3 genomes

AF:

0.392

AC:

59434

AN:

151810

Hom.:

12852

Cov.:

show subpopulations

Gnomad AFR

AF:

0.212

Gnomad AMI

AF:

0.424

Gnomad AMR

AF:

0.417

Gnomad ASJ

AF:

0.318

Gnomad EAS

AF:

0.215

Gnomad SAS

AF:

0.424

Gnomad FIN

AF:

0.528

Gnomad MID

AF:

0.253

Gnomad NFE

AF:

0.489

Gnomad OTH

AF:

0.390

GnomAD2 exomes

AF:

0.426

AC:

107176

AN:

251470

AF XY:

0.432

show subpopulations

Gnomad AFR exome

AF:

0.204

Gnomad AMR exome

AF:

0.417

Gnomad ASJ exome

AF:

0.329

Gnomad EAS exome

AF:

0.198

Gnomad FIN exome

AF:

0.528

Gnomad NFE exome

AF:

0.487

Gnomad OTH exome

AF:

0.428

GnomAD4 exome

AF:

0.470

AC:

686512

AN:

1461782

Hom.:

164961

Cov.:

AF XY:

0.469

AC XY:

341410

AN XY:

727196

show subpopulations

African (AFR)

AF:

0.201

AC:

6714

AN:

33478

American (AMR)

AF:

0.415

AC:

18568

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.326

AC:

8524

AN:

26136

East Asian (EAS)

AF:

0.246

AC:

9776

AN:

39700

South Asian (SAS)

AF:

0.432

AC:

37274

AN:

86254

European-Finnish (FIN)

AF:

0.524

AC:

27987

AN:

53420

Middle Eastern (MID)

AF:

0.356

AC:

2055

AN:

5768

European-Non Finnish (NFE)

AF:

0.494

AC:

549442

AN:

1111908

Other (OTH)

AF:

0.433

AC:

26172

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

24747

49494

74242

98989

123736

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

15796

31592

47388

63184

78980

<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:

0.391

AC:

59468

AN:

151928

Hom.:

12850

Cov.:

AF XY:

0.391

AC XY:

29042

AN XY:

74208

show subpopulations

African (AFR)

AF:

0.212

AC:

8780

AN:

41436

American (AMR)

AF:

0.417

AC:

6356

AN:

15256

Ashkenazi Jewish (ASJ)

AF:

0.318

AC:

1102

AN:

3466

East Asian (EAS)

AF:

0.215

AC:

1109

AN:

5164

South Asian (SAS)

AF:

0.425

AC:

2043

AN:

4812

European-Finnish (FIN)

AF:

0.528

AC:

5566

AN:

10540

Middle Eastern (MID)

AF:

0.231

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.489

AC:

33234

AN:

67936

Other (OTH)

AF:

0.390

AC:

824

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1732

3464

5195

6927

8659

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

560

1120

1680

2240

2800

<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:

0.442

Hom.:

53637

Bravo

AF:

0.370

TwinsUK

AF:

0.497

AC:

1842

ALSPAC

AF:

0.485

AC:

1868

ESP6500AA

AF:

0.222

AC:

977

ESP6500EA

AF:

0.480

AC:

4126

ExAC

AF:

0.426

AC:

51700

Asia WGS

AF:

0.303

AC:

1053

AN:

3478

EpiCase

AF:

0.478

EpiControl

AF:

0.469

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

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

- -

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.Ser707Asn in exon 12 of MYPN: This variant is not expected to have clinical si gnificance because it has been identified in 48% (4126/8600) of European America n chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.ed u/EVS/; dbSNP rs7916821). -

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

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Apr 27, 2012

Leiden Muscular Dystrophy (MYPN)

Significance:not provided

Review Status:no classification provided

Collection Method:curation

- -

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

0.15

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.54

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.024

.;.;.;T

Eigen

Benign

-0.20

Eigen_PC

Benign

-0.052

FATHMM_MKL

Benign

0.40

LIST_S2

Benign

0.78

T;T;.;T

MetaRNN

Benign

0.0014

T;T;T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

1.6

L;.;L;.

PhyloP100

0.84

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.25

N;N;N;.

REVEL

Benign

0.097

Sift

Benign

0.27

T;T;T;.

Sift4G

Benign

0.31

T;T;T;T

Polyphen

0.026

B;B;B;.

Vest4

0.046

MPC

0.13

ClinPred

0.0042

GERP RS

4.7

Varity_R

0.070

gMVP

0.11

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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