rs10823148

Positions:

chr10-68166577-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_032578.4(MYPN):c.1884C>G(p.Phe628Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.483 in 1,613,842 control chromosomes in the GnomAD database, including 196,299 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.40 ( 13839 hom., cov: 31)

Exomes 𝑓: 0.49 ( 182460 hom. )

Consequence

MYPN
NM_032578.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.71

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=3.222823E-4).

BP6

Variant 10-68166577-C-G is Benign according to our data. Variant chr10-68166577-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 31804.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-68166577-C-G is described in Lovd as [Benign]. Variant chr10-68166577-C-G is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.513 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYPN	NM_032578.4 linkuse as main transcript	c.1884C>G	p.Phe628Leu	missense_variant	10/20	ENST00000358913.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYPN	ENST00000358913.10 linkuse as main transcript	c.1884C>G	p.Phe628Leu	missense_variant	10/20	1	NM_032578.4	P1	Q86TC9-1

Frequencies

GnomAD3 genomes

AF:

0.396

AC:

60141

AN:

151876

Hom.:

13846

Cov.:

show subpopulations

Gnomad AFR

AF:

0.167

Gnomad AMI

AF:

0.532

Gnomad AMR

AF:

0.434

Gnomad ASJ

AF:

0.314

Gnomad EAS

AF:

0.212

Gnomad SAS

AF:

0.436

Gnomad FIN

AF:

0.546

Gnomad MID

AF:

0.259

Gnomad NFE

AF:

0.518

Gnomad OTH

AF:

0.391

GnomAD3 exomes

AF:

0.440

AC:

110543

AN:

251344

Hom.:

26261

AF XY:

0.447

AC XY:

60687

AN XY:

135842

show subpopulations

Gnomad AFR exome

AF:

0.157

Gnomad AMR exome

AF:

0.431

Gnomad ASJ exome

AF:

0.328

Gnomad EAS exome

AF:

0.195

Gnomad SAS exome

AF:

0.436

Gnomad FIN exome

AF:

0.544

Gnomad NFE exome

AF:

0.513

Gnomad OTH exome

AF:

0.443

GnomAD4 exome

AF:

0.492

AC:

719955

AN:

1461848

Hom.:

182460

Cov.:

AF XY:

0.492

AC XY:

357766

AN XY:

727228

show subpopulations

Gnomad4 AFR exome

AF:

0.152

Gnomad4 AMR exome

AF:

0.429

Gnomad4 ASJ exome

AF:

0.326

Gnomad4 EAS exome

AF:

0.239

Gnomad4 SAS exome

AF:

0.443

Gnomad4 FIN exome

AF:

0.540

Gnomad4 NFE exome

AF:

0.523

Gnomad4 OTH exome

AF:

0.448

GnomAD4 genome

AF:

0.396

AC:

60150

AN:

151994

Hom.:

13839

Cov.:

AF XY:

0.396

AC XY:

29416

AN XY:

74304

show subpopulations

Gnomad4 AFR

AF:

0.167

Gnomad4 AMR

AF:

0.433

Gnomad4 ASJ

AF:

0.314

Gnomad4 EAS

AF:

0.211

Gnomad4 SAS

AF:

0.436

Gnomad4 FIN

AF:

0.546

Gnomad4 NFE

AF:

0.518

Gnomad4 OTH

AF:

0.391

Alfa

AF:

0.475

Hom.:

13584

Bravo

AF:

0.372

TwinsUK

AF:

0.530

AC:

1966

ALSPAC

AF:

0.512

AC:

1973

ESP6500AA

AF:

0.174

AC:

768

ESP6500EA

AF:

0.510

AC:

4382

ExAC

AF:

0.438

AC:

53153

Asia WGS

AF:

0.298

AC:

1037

AN:

3478

EpiCase

AF:

0.503

EpiControl

AF:

0.493

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

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 29, 2014	p.Phe628Leu in exon 11 of MYPN: This variant is not expected to have clinical si gnificance because it has been identified in 51% (4382/8600) of European America n chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.ed u/EVS/; dbSNP rs10823148). -
Benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	May 13, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 04, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 13, 2013	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. -
Benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -

Dilated cardiomyopathy 1KK

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not provided

Benign:1Other:1

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
not provided, no classification provided	curation	Leiden Muscular Dystrophy (MYPN)	Apr 27, 2012	- -

MYPN-related myopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 16, 2015

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

Uncertain

0.55

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.49

CADD

Benign

DANN

Benign

0.65

DEOGEN2

Benign

0.020

.;.;.;T

Eigen

Benign

-0.28

Eigen_PC

Benign

-0.13

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.74

T;T;.;T

MetaRNN

Benign

0.00032

T;T;T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

0.83

L;.;L;.

MutationTaster

Benign

0.060

P;P;P

PrimateAI

Benign

0.44

PROVEAN

Benign

-0.33

N;N;N;.

REVEL

Benign

0.058

Sift

Benign

0.56

T;T;T;.

Sift4G

Benign

0.72

T;T;T;T

Polyphen

0.0010

B;B;B;.

Vest4

0.12

MutPred

0.27

Loss of sheet (P = 0.0181);.;Loss of sheet (P = 0.0181);.;

MPC

0.16

ClinPred

0.0097

GERP RS

4.3

Varity_R

0.097

gMVP

0.26

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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