NM_032578.4:c.59A>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS1

The NM_032578.4(MYPN):c.59A>G(p.Tyr20Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00165 in 1,614,190 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0017 ( 1 hom. )

Consequence

MYPN
NM_032578.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:9B:9O:1

Conservation

PhyloP100: 8.68

Publications

24 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 -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.1474685).

BP6

Variant 10-68121497-A-G is Benign according to our data. Variant chr10-68121497-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 31811.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00127 (193/152340) while in subpopulation AMR AF = 0.00216 (33/15298). AF 95% confidence interval is 0.00163. There are 0 homozygotes in GnomAd4. There are 81 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYPN	NM_032578.4 link	c.59A>G	p.Tyr20Cys	missense_variant	Exon 2 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.59A>G	p.Tyr20Cys	missense_variant	Exon 2 of 20	1	NM_032578.4	ENSP00000351790.5		Q86TC9-1

Frequencies

GnomAD3 genomes

AF:

0.00127

AC:

193

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000700

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00216

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00190

Gnomad OTH

AF:

0.000956

GnomAD2 exomes

AF:

0.000955

AC:

240

AN:

251372

AF XY:

0.000942

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.00139

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00161

Gnomad OTH exome

AF:

0.000653

GnomAD4 exome

AF:

0.00169

AC:

2466

AN:

1461850

Hom.:

Cov.:

AF XY:

0.00164

AC XY:

1195

AN XY:

727218

show subpopulations

African (AFR)

AF:

0.000269

AC:

AN:

33478

American (AMR)

AF:

0.00136

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000464

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.0000562

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00206

AC:

2287

AN:

1111978

Other (OTH)

AF:

0.00166

AC:

100

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

131

261

392

522

653

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

192

288

384

480

<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:

0.00127

AC:

193

AN:

152340

Hom.:

Cov.:

AF XY:

0.00109

AC XY:

AN XY:

74492

show subpopulations

African (AFR)

AF:

0.000697

AC:

AN:

41578

American (AMR)

AF:

0.00216

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00190

AC:

129

AN:

68036

Other (OTH)

AF:

0.000946

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00158

Hom.:

Bravo

AF:

0.00146

TwinsUK

AF:

0.00270

AC:

ALSPAC

AF:

0.00182

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00116

AC:

ExAC

AF:

0.000914

AC:

111

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00153

EpiControl

AF:

0.00148

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:9Benign:9Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3Benign:3Other:1

Nov 16, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 23299917, 23861362, 22286171, 26688388, 27171814, 28082330, 26899768, 26498160, 27896284, 22892539, 29875424, 30847666, 32880476) -

Apr 12, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BS1, PS3_moderate -

Apr 27, 2012

Leiden Muscular Dystrophy (MYPN)

Significance:not provided

Review Status:no classification provided

Collection Method:curation

- -

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

Nov 19, 2015

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

MYPN: PM2:Supporting, PP3 -

Dec 01, 2023

Revvity Omics, Revvity

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dilated cardiomyopathy 1KK

Pathogenic:2Uncertain:1Benign:1

Jun 27, 2013

ClinVar Staff, National Center for Biotechnology Information (NCBI)

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 29, 2016

Division of Human Genetics, Children's Hospital of Philadelphia

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:research

- -

May 01, 2012

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

not specified

Uncertain:2Benign:2

Apr 21, 2017

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 13, 2019

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Tyr20Cys variant (rs140148105) was reported in two patients with either HCM or DCM (Purevjav 2012) and one with DCM who had undergone heart transplant surgery (Cuenca 2016). This variant is listed in the Genome Aggregation Database (gnomAD) with a frequency of 0.15 percent in the European Non-Finnish population (identified on 200 out of 129,122 chromosomes) and has been reported to the ClinVar database (Variation ID: 31811). This variant was reported to change expression of human MYPN binding proteins and resulted in hypertrophy of the mouse heart (Purevjav 2012). The tyrosine at position 20 is highly conserved and computational analyses of the effects of the p.Tyr20Cys variant on protein structure and function provide conflicting results (SIFT: tolerated, PolyPhen-2: probably damaging). Altogether, there is not enough evidence to classify the p.Tyr20Cys variant with certainty. References: Cuenca S et al. Genetic basis of familial dilated cardiomyopathy patients undergoing heart transplantation. J Heart Lung Transplant. 2016 May;35(5):625-35. Purevjav E et al. Molecular basis for clinical heterogeneity in inherited cardiomyopathies due to myopalladin mutations. Hum Mol Genet. 2012 May 1;21(9):2039-53. -

Dec 18, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Tyr20Cys variant in MYPN is classified as likely benign because it has bee n identified in 0.15% (200/129122) of European chromosomes by gnomAD (http://gno mad.broadinstitute.org). ACMG/AMP criteria applied: PP3, PS3_P, BS1 -

Mar 31, 2024

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Primary dilated cardiomyopathy

Uncertain:1Benign:2

Aug 29, 2017

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 26, 2021

Loeys Lab, Universiteit Antwerpen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change results in a missense variant in the MYPN gene (p.(Tyr20Cys)). This variant is present in population databases with a prevalence of 264/282778 in GnomAD (BS1). The variant affects a highly conserved nucleotide and highly conserved amino acid. This variant has been reported in the literature. It has been identified in several unrelated individuals with DCM or HCM (PMID: 22286171). In a mouse model the variant resulted in the development of HCM, disruption of intercalated discs and disturbed expression of desmin, desmoplakin, connexin 43 and vinculin, leading to abnormal assembly of the terminal Z-disc(PMID: 22286171) (PS3). Prediction programs predict a pathogenic effect (Align GVGD C65, pathogenic; Polyphen-2-HumDiv: probably damaging; Polyphen-2-HumVar: probably damaging; SIFT: deleterious; Mutation Taster: disease causing) (PP3). The variant was identified in 3 unrelated patients. The first had DCM and an additional TMEM c.1073C>T variant (classified as pathogenic, BP5), a second patient presented with DCM and a third patient presented with HCM and carried an additional MYBPC3 variant (c.1227-2A>G, classified as likely pathogenic). No data on segregation are available. In conclusion this variant was classified as a variant of unknown significance according to ACMG-guidelines (the criteria for benign and pathogenic are contradictory: BS1; BP5; PS3; PP3). -

Oct 09, 2014

Blueprint Genetics

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Dilated cardiomyopathy 1KK;C4479186:MYPN-related myopathy

Uncertain:2

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

MYPN NM_032578.3 exon 2 p.Tyr20Cys (c.59A>G): This variant has been reported in the literature in two individuals with DCM and in one individual with HCM (Purevjav 2012 PMID 22286171; Cuenca 2016 PMID 26899768). However, this variant is also present in 0.1% (200/129122) of European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/10-69881254-A-G) and is present in ClinVar, with classifications ranging from likely benign to likely pathogenic (Variation ID:31811). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In addition, an in vivo functional study using transgenic mice supports a deleterious effect of this variant (Purevjav 2012 PMID 22286171). In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Jun 22, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

Familial hypertrophic cardiomyopathy 22

Pathogenic:1

May 01, 2012

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Cardiovascular phenotype

Benign:1

May 07, 2018

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely 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

0.42

BayesDel_addAF

Uncertain

0.063

BayesDel_noAF

Pathogenic

0.31

CADD

Uncertain

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

0.78

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.92

D;.;D

M_CAP

Benign

0.076

MetaRNN

Benign

0.15

T;T;T

MetaSVM

Uncertain

0.11

MutationAssessor

Benign

2.0

M;M;M

PhyloP100

8.7

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

-2.3

N;N;N

REVEL

Uncertain

0.53

Sift

Uncertain

0.0020

D;D;D

Sift4G

Uncertain

0.030

D;D;D

Polyphen

1.0

D;D;D

Vest4

0.83

MVP

0.94

MPC

0.68

ClinPred

0.059

GERP RS

6.0

PromoterAI

0.036

Neutral

(source)

Varity_R

0.38

gMVP

0.60

Mutation Taster

=14/86

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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