rs62620248

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_032578.4(MYPN):c.2410G>A(p.Gly804Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0253 in 1,613,978 control chromosomes in the GnomAD database, including 656 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. G804G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.018 ( 33 hom., cov: 32)

Exomes 𝑓: 0.026 ( 623 hom. )

Consequence

MYPN
NM_032578.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12O:1

Conservation

PhyloP100: 2.15

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=0.0081009865).

BP6

Variant 10-68174502-G-A is Benign according to our data. Variant chr10-68174502-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 31809.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-68174502-G-A is described in Lovd as [Benign]. Variant chr10-68174502-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0181 (2749/152144) while in subpopulation NFE AF= 0.0285 (1936/68006). AF 95% confidence interval is 0.0274. There are 33 homozygotes in gnomad4. There are 1224 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 2749 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYPN	NM_032578.4 linkuse as main transcript	c.2410G>A	p.Gly804Arg	missense_variant	11/20	ENST00000358913.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYPN	ENST00000358913.10 linkuse as main transcript	c.2410G>A	p.Gly804Arg	missense_variant	11/20	1	NM_032578.4	P1	Q86TC9-1

Frequencies

GnomAD3 genomes

AF:

0.0181

AC:

2749

AN:

152026

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00503

Gnomad AMI

AF:

0.00989

Gnomad AMR

AF:

0.0209

Gnomad ASJ

AF:

0.0314

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00353

Gnomad FIN

AF:

0.0103

Gnomad MID

AF:

0.0316

Gnomad NFE

AF:

0.0285

Gnomad OTH

AF:

0.0153

GnomAD3 exomes

AF:

0.0183

AC:

4584

AN:

251128

Hom.:

AF XY:

0.0181

AC XY:

2451

AN XY:

135714

show subpopulations

Gnomad AFR exome

AF:

0.00443

Gnomad AMR exome

AF:

0.0139

Gnomad ASJ exome

AF:

0.0261

Gnomad EAS exome

AF:

0.0000545

Gnomad SAS exome

AF:

0.00438

Gnomad FIN exome

AF:

0.0102

Gnomad NFE exome

AF:

0.0290

Gnomad OTH exome

AF:

0.0199

GnomAD4 exome

AF:

0.0260

AC:

38079

AN:

1461834

Hom.:

623

Cov.:

AF XY:

0.0255

AC XY:

18567

AN XY:

727216

show subpopulations

Gnomad4 AFR exome

AF:

0.00418

Gnomad4 AMR exome

AF:

0.0150

Gnomad4 ASJ exome

AF:

0.0273

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.00444

Gnomad4 FIN exome

AF:

0.0114

Gnomad4 NFE exome

AF:

0.0306

Gnomad4 OTH exome

AF:

0.0241

GnomAD4 genome

AF:

0.0181

AC:

2749

AN:

152144

Hom.:

Cov.:

AF XY:

0.0165

AC XY:

1224

AN XY:

74404

show subpopulations

Gnomad4 AFR

AF:

0.00501

Gnomad4 AMR

AF:

0.0208

Gnomad4 ASJ

AF:

0.0314

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00374

Gnomad4 FIN

AF:

0.0103

Gnomad4 NFE

AF:

0.0285

Gnomad4 OTH

AF:

0.0157

Alfa

AF:

0.0260

Hom.:

Bravo

AF:

0.0180

TwinsUK

AF:

0.0345

AC:

128

ALSPAC

AF:

0.0267

AC:

103

ESP6500AA

AF:

0.00409

AC:

ESP6500EA

AF:

0.0350

AC:

301

ExAC

AF:

0.0184

AC:

2231

Asia WGS

AF:

0.00318

AC:

AN:

3478

EpiCase

AF:

0.0278

EpiControl

AF:

0.0306

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Jun 13, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 09, 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. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 17, 2023	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 13, 2015	p.Gly804Arg in exon 12 of MYPN: This variant is not expected to have clinical si gnificance because it has been identified in 3.5% (301/8600) of European America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs62620248). -

Dilated cardiomyopathy 1KK

Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
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	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -

not provided

Benign:1Other:1

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 26, 2023	- -
not provided, no classification provided	curation	Leiden Muscular Dystrophy (MYPN)	Apr 27, 2012	- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 15, 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

0.28

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.50

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.014

.;.;.;T

Eigen

Uncertain

0.31

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Uncertain

0.84

LIST_S2

Uncertain

0.91

D;D;.;D

MetaRNN

Benign

0.0081

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.9

M;.;M;.

MutationTaster

Benign

0.88

N;N;N

PrimateAI

Benign

0.44

PROVEAN

Benign

0.23

N;N;N;.

REVEL

Benign

0.086

Sift

Benign

0.042

D;D;T;.

Sift4G

Benign

0.56

T;T;T;T

Polyphen

0.92

P;P;P;.

Vest4

0.39

MutPred

0.32

Loss of glycosylation at S803 (P = 0.0747);.;Loss of glycosylation at S803 (P = 0.0747);.;

MPC

0.17

ClinPred

0.019

GERP RS

5.8

Varity_R

0.11

gMVP

0.35

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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