chr10-68199417-C-T

Position:

chr10-68199417-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_032578.4(MYPN):c.3335C>T(p.Pro1112Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00241 in 1,614,168 control chromosomes in the GnomAD database, including 17 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 0.0025 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0024 ( 14 hom. )

Consequence

MYPN
NM_032578.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:2B:17O:1

Conservation

PhyloP100: 6.01

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010449231).

BP6

Variant 10-68199417-C-T is Benign according to our data. Variant chr10-68199417-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 31791.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, Uncertain_significance=1, not_provided=1, Benign=5}. Variant chr10-68199417-C-T is described in Lovd as [Pathogenic]. Variant chr10-68199417-C-T is described in Lovd as [Likely_pathogenic]. Variant chr10-68199417-C-T is described in Lovd as [Benign]. Variant chr10-68199417-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00249 (379/152322) while in subpopulation SAS AF= 0.00517 (25/4832). AF 95% confidence interval is 0.00407. There are 3 homozygotes in gnomad4. There are 198 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 379 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYPN	NM_032578.4 linkuse as main transcript	c.3335C>T	p.Pro1112Leu	missense_variant	17/20	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.3335C>T	p.Pro1112Leu	missense_variant	17/20	1	NM_032578.4	ENSP00000351790.5		Q86TC9-1

Frequencies

GnomAD3 genomes

AF:

0.00248

AC:

377

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00125

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00497

Gnomad ASJ

AF:

0.0121

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00517

Gnomad FIN

AF:

0.000660

Gnomad MID

AF:

0.0380

Gnomad NFE

AF:

0.00223

Gnomad OTH

AF:

0.00527

GnomAD3 exomes

AF:

0.00318

AC:

800

AN:

251290

Hom.:

AF XY:

0.00359

AC XY:

488

AN XY:

135818

show subpopulations

Gnomad AFR exome

AF:

0.00148

Gnomad AMR exome

AF:

0.00361

Gnomad ASJ exome

AF:

0.00973

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.00588

Gnomad FIN exome

AF:

0.000601

Gnomad NFE exome

AF:

0.00277

Gnomad OTH exome

AF:

0.00701

GnomAD4 exome

AF:

0.00240

AC:

3509

AN:

1461846

Hom.:

Cov.:

AF XY:

0.00254

AC XY:

1849

AN XY:

727222

show subpopulations

Gnomad4 AFR exome

AF:

0.00170

Gnomad4 AMR exome

AF:

0.00380

Gnomad4 ASJ exome

AF:

0.00999

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00605

Gnomad4 FIN exome

AF:

0.000655

Gnomad4 NFE exome

AF:

0.00187

Gnomad4 OTH exome

AF:

0.00394

GnomAD4 genome

AF:

0.00249

AC:

379

AN:

152322

Hom.:

Cov.:

AF XY:

0.00266

AC XY:

198

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.00128

Gnomad4 AMR

AF:

0.00497

Gnomad4 ASJ

AF:

0.0121

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00517

Gnomad4 FIN

AF:

0.000660

Gnomad4 NFE

AF:

0.00223

Gnomad4 OTH

AF:

0.00569

Alfa

AF:

0.00268

Hom.:

Bravo

AF:

0.00250

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.00182

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.00244

AC:

ExAC

AF:

0.00303

AC:

368

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.00393

EpiControl

AF:

0.00421

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:2Benign:17Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:6

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 15, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Jun 22, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 17, 2017	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. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 19, 2023	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 11, 2015	p.Pro1112Leu in exon 18 of MYPN: This variant is not expected to have clinical s ignificance because it has been identified in 0.6% (93/16504) of South Asian chr omosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.o rg; dbSNP rs71534278). -

not provided

Benign:5Other:1

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 23, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
not provided, no classification provided	curation	Leiden Muscular Dystrophy (MYPN)	Apr 27, 2012	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	MYPN: BS2 -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Dilated cardiomyopathy 1KK

Pathogenic:2Benign:2

Benign, criteria provided, single submitter	clinical testing	Mendelics	Aug 22, 2023	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 2012	- -
Likely pathogenic, no assertion criteria provided	literature only	ClinVar Staff, National Center for Biotechnology Information (NCBI)	Jun 27, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Primary dilated cardiomyopathy

Benign:2

Likely benign, no assertion criteria provided	clinical testing	Blueprint Genetics	Jun 25, 2014	- -
Likely benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -

Familial hypertrophic cardiomyopathy 22

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 01, 2012

- -

Hypertrophic cardiomyopathy

Uncertain:1

Uncertain significance, no assertion criteria provided

research

Zaffran Lab, Genetics of Cardiac Diseases Laboratory, Marseille Medical Genetics

- -

Hypertrophic cardiomyopathy;C0878544:Cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

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

May 23, 2018

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 14, 2017

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

0.17

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Uncertain

0.0

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.12

.;.;.;T

Eigen

Uncertain

0.58

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.96

D;D;.;D

M_CAP

Benign

0.045

MetaRNN

Benign

0.010

T;T;T;T

MetaSVM

Benign

-0.65

MutationAssessor

Benign

1.2

L;.;L;.

PrimateAI

Uncertain

0.56

PROVEAN

Pathogenic

-5.4

D;D;D;.

REVEL

Uncertain

0.45

Sift

Benign

0.053

T;T;T;.

Sift4G

Uncertain

0.010

D;D;D;D

Polyphen

1.0

D;D;D;.

Vest4

0.54

MVP

0.82

MPC

0.62

ClinPred

0.021

GERP RS

5.4

Varity_R

0.41

gMVP

0.49

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.14

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