10-68121497-A-G

Position:

chr10-68121497-A-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_ModerateBS1BS2

The NM_001256268.2(MYPN):c.-1064A>G variant causes a 5 prime UTR premature start codon gain 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_001256268.2 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:8B:9O:1

Conservation

PhyloP100: 8.68

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 links:

MYPN (HGNC:):

MYPN links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4

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

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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 193 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYPN	NM_032578.4 linkuse as main transcript	c.59A>G	p.Tyr20Cys	missense_variant	2/20	ENST00000358913.10	NP_115967.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYPN	ENST00000358913.10 linkuse as main transcript	c.59A>G	p.Tyr20Cys	missense_variant	2/20	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

GnomAD3 exomes

AF:

0.000955

AC:

240

AN:

251372

Hom.:

AF XY:

0.000942

AC XY:

128

AN XY:

135842

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 SAS 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

Gnomad4 AFR exome

AF:

0.000269

Gnomad4 AMR exome

AF:

0.00136

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.0000562

Gnomad4 NFE exome

AF:

0.00206

Gnomad4 OTH exome

AF:

0.00166

GnomAD4 genome

AF:

0.00127

AC:

193

AN:

152340

Hom.:

Cov.:

AF XY:

0.00109

AC XY:

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.000697

Gnomad4 AMR

AF:

0.00216

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00190

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.00196

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:8Benign:9Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3Benign:3Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 12, 2023	BS1, PS3_moderate -
Likely benign, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 01, 2023	- -
not provided, no classification provided	curation	Leiden Muscular Dystrophy (MYPN)	Apr 27, 2012	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	MYPN: PM2:Supporting, PP3 -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 19, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 16, 2020	This variant is associated with the following publications: (PMID: 23299917, 23861362, 22286171, 26688388, 27171814, 28082330, 26899768, 26498160, 27896284, 22892539, 29875424, 30847666, 32880476) -
Likely benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -

Dilated cardiomyopathy 1KK

Pathogenic:2Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Uncertain significance, no assertion criteria provided	research	Division of Human Genetics, Children's Hospital of Philadelphia	Apr 29, 2016	- -
Likely pathogenic, no assertion criteria provided	literature only	ClinVar Staff, National Center for Biotechnology Information (NCBI)	Jun 27, 2013	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 2012	- -

not specified

Uncertain:2Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 13, 2019	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Apr 21, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 18, 2018	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 -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 31, 2024	- -

Primary dilated cardiomyopathy

Uncertain:1Benign:2

Likely benign, no assertion criteria provided	clinical testing	Blueprint Genetics	Oct 09, 2014	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Loeys Lab, Universiteit Antwerpen	Feb 26, 2021	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). -
Likely benign, criteria provided, single submitter	clinical testing	Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	Aug 29, 2017	- -

Familial hypertrophic cardiomyopathy 22

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 01, 2012

- -

Dilated cardiomyopathy 1KK;C4479186:MYPN-related myopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Mar 30, 2021

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. -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 07, 2018

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

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

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

Varity_R

0.38

gMVP

0.60

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over