rs138313730

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_032578.4(MYPN):c.3481C>A(p.Leu1161Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00101 in 1,607,316 control chromosomes in the GnomAD database, including 21 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 ( 4 hom., cov: 31)

Exomes 𝑓: 0.00098 ( 17 hom. )

Consequence

MYPN
NM_032578.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:15O:1

Conservation

PhyloP100: 5.03

Publications

9 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008320689).

BP6

Variant 10-68199563-C-A is Benign according to our data. Variant chr10-68199563-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 31819.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0013 (189/145522) while in subpopulation AMR AF = 0.00775 (111/14322). AF 95% confidence interval is 0.00658. There are 4 homozygotes in GnomAd4. There are 85 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYPN	NM_032578.4 link	c.3481C>A	p.Leu1161Ile	missense_variant	Exon 17 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.3481C>A	p.Leu1161Ile	missense_variant	Exon 17 of 20	1	NM_032578.4	ENSP00000351790.5		Q86TC9-1

Frequencies

GnomAD3 genomes

AF:

0.00130

AC:

189

AN:

145398

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000824

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00769

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00535

Gnomad SAS

AF:

0.00112

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000199

Gnomad OTH

AF:

0.000505

GnomAD2 exomes

AF:

0.00381

AC:

957

AN:

251238

AF XY:

0.00305

show subpopulations

Gnomad AFR exome

AF:

0.000431

Gnomad AMR exome

AF:

0.0227

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00506

Gnomad FIN exome

AF:

0.000185

Gnomad NFE exome

AF:

0.000167

Gnomad OTH exome

AF:

0.00473

GnomAD4 exome

AF:

0.000977

AC:

1428

AN:

1461794

Hom.:

Cov.:

AF XY:

0.000887

AC XY:

645

AN XY:

727208

show subpopulations

African (AFR)

AF:

0.000358

AC:

AN:

33480

American (AMR)

AF:

0.0196

AC:

877

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00527

AC:

209

AN:

39696

South Asian (SAS)

AF:

0.000754

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.000318

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000182

AC:

202

AN:

1111930

Other (OTH)

AF:

0.000745

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

166

249

332

415

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

130

<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:

0.00130

AC:

189

AN:

145522

Hom.:

Cov.:

AF XY:

0.00120

AC XY:

AN XY:

70734

show subpopulations

African (AFR)

AF:

0.000822

AC:

AN:

40148

American (AMR)

AF:

0.00775

AC:

111

AN:

14322

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3426

East Asian (EAS)

AF:

0.00516

AC:

AN:

5038

South Asian (SAS)

AF:

0.00112

AC:

AN:

4456

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9684

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.000199

AC:

AN:

65278

Other (OTH)

AF:

0.000500

AC:

AN:

2002

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

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:

0.000963

Hom.:

Bravo

AF:

0.00254

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.00330

AC:

400

Asia WGS

AF:

0.00318

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:15Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:6Other:1

Feb 07, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Identified in a patient with HCM in the published literature (Purevjav et al., 2012); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23299917, 22286171, 27535533) -

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

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 27, 2012

Leiden Muscular Dystrophy (MYPN)

Significance:not provided

Review Status:no classification provided

Collection Method:curation

- -

Aug 11, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

MYPN: BS1, BS2 -

Oct 13, 2016

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:provider interpretation

p.Leu1161Ile (c.3481 C>A) in the MYPN gene Given the weak disease-gene association, the weak case data, and the presence in ancestry-matched general population samples, we consider this variant a variant of uncertain significance. MYPN (NM_032578.2) encodes myopalladin, a protein component of the sarcomere. Heterozygous mutations in MYPN have been reported in hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM) and restrictive cardiomyopathy (RCM) (Purevjav et al. 2012 Hum Molec Genet 21(9):2039-2053; Meyer et al. 2012 Eur J Hum Genet Epub ahead of print). However, when Megan Grove from our team reviewed the supporting data in 2012 we felt that it was weak. The variant has been seen in at least 1 unrelated case of hypertrophic cardiomyopathy (not including this patient's family). There is no segregation data available. Purevjav et al (2012) observed the variant in an American Indian/Alaskan male with HCM who had undergone myectomy. In silico analysis with PolyPhen-2 predicts the variant to be damaging. The variant occurs in the alpha-actinin binding domain. This is a conservative amino acid change from nonpolar leucine to a nonpolar isoleucine at a residue that is highly conserved across vertebrate species (it is a nonpolar phenylalanine in squirrel). It is predicted to be "probably damaging" and "tolerated" by PolyPhen and SIFT in silico analyses, respectively. [UPDATED in 2016] In total the variant has not been seen in at least 400 of >60,000 published controls and individuals from publicly available population datasets. It is present in 400 individuals in ExAC, across multiple ethnicities. The variant was reported in 3 of 4300 Caucasian individuals and 0 of 2203 African-American individuals in the NHLBI Exome Sequencing Project dataset (as of September 12th, 2014). The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. Note that other variants with strong evidence for pathogenicity have been seen at similar frequencies in this dataset so this does not necessarily rule out pathogenicity (Pan et al 2012). Per GeneDx, the variant was observed in the 1000 Genomes samples: 3/551 (0.5%) alleles from individuals of Asian background and in 1/349 (0.3%) alleles of individuals of Hispanic ancestry. The variant was not observed in the following published control samples: 1020 (Purejeav et al 2012). -

Dilated cardiomyopathy 1KK

Uncertain:2Benign:4

Jun 27, 2013

ClinVar Staff, National Center for Biotechnology Information (NCBI)

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 28, 2017

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 18, 2016

Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:reference population

- -

May 31, 2017

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

The heterozygous p.Leu1161Ile variant in MYPN has been identified in an American Indian Alaskan individual with hypertrophic cardiomyopathy (PMID: 22286171). This variant has also been identified in >2% of Latino chromosomes and 5 homozygotes by ExAC (http://gnomad.broadinstitute.org/), and in 3 individuals from the NHLBI GO Exome Sequencing Project (PMID: 23299917). In summary, this variant meets criteria to be classified as benign for hypertrophic cardiomyopathy. -

not specified

Benign:3

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 29, 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 03, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Leu1161Ile in exon 18 of MYPN: This variant is not expected to have clinical s ignificance because it has been identified in 2.8% (320/11566) of Latino chromos omes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs138313730). -

Primary familial dilated cardiomyopathy

Uncertain:1

Mar 28, 2017

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Primary dilated cardiomyopathy;C0018801:Heart failure;C0878544:Cardiomyopathy

Benign:1

Jan 24, 2019

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

- -

Cardiovascular phenotype

Benign:1

Apr 25, 2016

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

0.20

BayesDel_addAF

Benign

-0.088

BayesDel_noAF

Uncertain

0.12

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.090

.;.;.;T

Eigen

Pathogenic

0.77

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.94

D;D;.;D

MetaRNN

Benign

0.0083

T;T;T;T

MetaSVM

Uncertain

0.41

MutationAssessor

Benign

1.9

L;.;L;.

PhyloP100

5.0

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-1.7

N;N;N;.

REVEL

Pathogenic

0.71

Sift

Benign

0.047

D;D;D;.

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

1.0

D;D;D;.

Vest4

0.64

MVP

0.86

MPC

0.64

ClinPred

0.038

GERP RS

5.4

Varity_R

0.41

gMVP

0.37

Mutation Taster

=82/18

polymorphism

(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