10-68122281-A-G

Position:

chr10-68122281-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_032578.4(MYPN):c.843A>G(p.Pro281=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00644 in 1,613,930 control chromosomes in the GnomAD database, including 519 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.033 ( 271 hom., cov: 32)

Exomes 𝑓: 0.0037 ( 248 hom. )

Consequence

MYPN
NM_032578.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9O:1

Conservation

PhyloP100: -0.543

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.64).

BP6

Variant 10-68122281-A-G is Benign according to our data. Variant chr10-68122281-A-G is described in ClinVar as [Benign]. Clinvar id is 31826.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-68122281-A-G is described in Lovd as [Benign]. Variant chr10-68122281-A-G is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=-0.543 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.11 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.843A>G	p.Pro281=	synonymous_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.843A>G	p.Pro281=	synonymous_variant	2/20	1	NM_032578.4	ENSP00000351790	P1	Q86TC9-1

Frequencies

GnomAD3 genomes

AF:

0.0327

AC:

4982

AN:

152178

Hom.:

270

Cov.:

show subpopulations

Gnomad AFR

AF:

0.112

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0142

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.000603

Gnomad OTH

AF:

0.0272

GnomAD3 exomes

AF:

0.00883

AC:

2207

AN:

249860

Hom.:

112

AF XY:

0.00672

AC XY:

910

AN XY:

135348

show subpopulations

Gnomad AFR exome

AF:

0.116

Gnomad AMR exome

AF:

0.00796

Gnomad ASJ exome

AF:

0.000199

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.000786

Gnomad NFE exome

AF:

0.000469

Gnomad OTH exome

AF:

0.00625

GnomAD4 exome

AF:

0.00369

AC:

5398

AN:

1461634

Hom.:

248

Cov.:

AF XY:

0.00326

AC XY:

2371

AN XY:

727096

show subpopulations

Gnomad4 AFR exome

AF:

0.118

Gnomad4 AMR exome

AF:

0.00828

Gnomad4 ASJ exome

AF:

0.000230

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000162

Gnomad4 FIN exome

AF:

0.000431

Gnomad4 NFE exome

AF:

0.000457

Gnomad4 OTH exome

AF:

0.00826

GnomAD4 genome

AF:

0.0328

AC:

5002

AN:

152296

Hom.:

271

Cov.:

AF XY:

0.0323

AC XY:

2409

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.113

Gnomad4 AMR

AF:

0.0142

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000621

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.000603

Gnomad4 OTH

AF:

0.0270

Alfa

AF:

0.0158

Hom.:

Bravo

AF:

0.0391

Asia WGS

AF:

0.00779

AC:

AN:

3478

EpiCase

AF:

0.000600

EpiControl

AF:

0.000474

ClinVar

Significance: Benign

Submissions summary: Benign:9Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

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	GeneDx	Jan 24, 2014	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	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 13, 2015	p.Pro281Pro in exon 3 of MYPN: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue and is not located wit hin the splice consensus sequence. It has been identified in 10.3% (453/4406) of African American chromosomes from a broad population by the NHLBI Exome Sequenc ing Project (http://evs.gs.washington.edu/EVS; dbSNP rs74143022). -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Dilated cardiomyopathy 1KK

Benign:2

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

Jul 08, 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. -

Dilated cardiomyopathy 1KK;C4479186:MYPN-related myopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 20, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.64

CADD

Benign

7.9

DANN

Benign

0.76

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