rs74143030

Positions:

Variant summary

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

The NM_032578.4(MYPN):c.1399G>A(p.Glu467Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00772 in 1,610,680 control chromosomes in the GnomAD database, including 761 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.040 ( 398 hom., cov: 32)

Exomes 𝑓: 0.0044 ( 363 hom. )

Consequence

MYPN
NM_032578.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11O:1

Conservation

PhyloP100: 7.69

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0025645792).

BP6

Variant 10-68158567-G-A is Benign according to our data. Variant chr10-68158567-G-A is described in ClinVar as [Benign]. Clinvar id is 31827.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-68158567-G-A is described in Lovd as [Benign]. Variant chr10-68158567-G-A is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.134 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYPN	NM_032578.4 linkuse as main transcript	c.1399G>A	p.Glu467Lys	missense_variant	7/20	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.1399G>A	p.Glu467Lys	missense_variant	7/20	1	NM_032578.4	ENSP00000351790.5		Q86TC9-1

Frequencies

GnomAD3 genomes

AF:

0.0399

AC:

6072

AN:

152162

Hom.:

398

Cov.:

show subpopulations

Gnomad AFR

AF:

0.137

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0177

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.000617

Gnomad OTH

AF:

0.0312

GnomAD3 exomes

AF:

0.0110

AC:

2755

AN:

251286

Hom.:

168

AF XY:

0.00797

AC XY:

1083

AN XY:

135814

show subpopulations

Gnomad AFR exome

AF:

0.144

Gnomad AMR exome

AF:

0.00897

Gnomad ASJ exome

AF:

0.000198

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000352

Gnomad OTH exome

AF:

0.00767

GnomAD4 exome

AF:

0.00436

AC:

6364

AN:

1458400

Hom.:

363

Cov.:

AF XY:

0.00387

AC XY:

2812

AN XY:

725718

show subpopulations

Gnomad4 AFR exome

AF:

0.145

Gnomad4 AMR exome

AF:

0.0101

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000336

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000371

Gnomad4 OTH exome

AF:

0.00951

GnomAD4 genome

AF:

0.0399

AC:

6076

AN:

152280

Hom.:

398

Cov.:

AF XY:

0.0383

AC XY:

2851

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.137

Gnomad4 AMR

AF:

0.0176

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000617

Gnomad4 OTH

AF:

0.0308

Alfa

AF:

0.00903

Hom.:

131

Bravo

AF:

0.0461

ESP6500AA

AF:

0.144

AC:

636

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.0137

AC:

1657

Asia WGS

AF:

0.00866

AC:

AN:

3478

EpiCase

AF:

0.000545

EpiControl

AF:

0.000474

ClinVar

Significance: Benign

Submissions summary: Benign:11Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 13, 2015	p.Glu467Lys in exon 8 of MYPN: This variant is not expected to have clinical sig nificance because it has been identified in 14.4% (636/4406) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs74143030). -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 10, 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:3

Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 19, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not provided

Benign:1Other:1

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

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 26, 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

Benign

0.31

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.24

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.020

.;.;.;T;.

Eigen

Benign

0.010

Eigen_PC

Benign

0.21

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.84

T;D;.;D;D

MetaRNN

Benign

0.0026

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.23

N;.;N;.;N

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-0.29

N;N;N;.;N

REVEL

Benign

0.20

Sift

Benign

0.41

T;T;T;.;T

Sift4G

Benign

0.71

T;T;T;T;T

Polyphen

0.48

P;B;P;.;P

Vest4

0.38

MPC

0.18

ClinPred

0.017

GERP RS

4.8

Varity_R

0.23

gMVP

0.51

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