rs61854624

Positions:

Variant summary

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

The NM_032578.4(MYPN):c.1869C>A(p.Thr623=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.158 in 1,613,976 control chromosomes in the GnomAD database, including 21,862 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.13 ( 1677 hom., cov: 31)

Exomes 𝑓: 0.16 ( 20185 hom. )

Consequence

MYPN
NM_032578.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7O:1

Conservation

PhyloP100: 0.0800

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.72).

BP6

Variant 10-68166562-C-A is Benign according to our data. Variant chr10-68166562-C-A is described in ClinVar as [Benign]. Clinvar id is 31803.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-68166562-C-A is described in Lovd as [Benign]. Variant chr10-68166562-C-A is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=0.08 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.179 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.1869C>A	p.Thr623=	synonymous_variant	10/20	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.1869C>A	p.Thr623=	synonymous_variant	10/20	1	NM_032578.4	ENSP00000351790	P1	Q86TC9-1

Frequencies

GnomAD3 genomes

AF:

0.129

AC:

19639

AN:

152028

Hom.:

1672

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0304

Gnomad AMI

AF:

0.127

Gnomad AMR

AF:

0.184

Gnomad ASJ

AF:

0.304

Gnomad EAS

AF:

0.0926

Gnomad SAS

AF:

0.150

Gnomad FIN

AF:

0.189

Gnomad MID

AF:

0.199

Gnomad NFE

AF:

0.159

Gnomad OTH

AF:

0.150

GnomAD3 exomes

AF:

0.165

AC:

41580

AN:

251312

Hom.:

3966

AF XY:

0.165

AC XY:

22413

AN XY:

135824

show subpopulations

Gnomad AFR exome

AF:

0.0295

Gnomad AMR exome

AF:

0.238

Gnomad ASJ exome

AF:

0.291

Gnomad EAS exome

AF:

0.0913

Gnomad SAS exome

AF:

0.158

Gnomad FIN exome

AF:

0.184

Gnomad NFE exome

AF:

0.162

Gnomad OTH exome

AF:

0.177

GnomAD4 exome

AF:

0.161

AC:

234964

AN:

1461830

Hom.:

20185

Cov.:

AF XY:

0.161

AC XY:

117159

AN XY:

727212

show subpopulations

Gnomad4 AFR exome

AF:

0.0257

Gnomad4 AMR exome

AF:

0.237

Gnomad4 ASJ exome

AF:

0.294

Gnomad4 EAS exome

AF:

0.0926

Gnomad4 SAS exome

AF:

0.159

Gnomad4 FIN exome

AF:

0.184

Gnomad4 NFE exome

AF:

0.160

Gnomad4 OTH exome

AF:

0.156

GnomAD4 genome

AF:

0.129

AC:

19660

AN:

152146

Hom.:

1677

Cov.:

AF XY:

0.132

AC XY:

9834

AN XY:

74364

show subpopulations

Gnomad4 AFR

AF:

0.0303

Gnomad4 AMR

AF:

0.185

Gnomad4 ASJ

AF:

0.304

Gnomad4 EAS

AF:

0.0923

Gnomad4 SAS

AF:

0.152

Gnomad4 FIN

AF:

0.189

Gnomad4 NFE

AF:

0.159

Gnomad4 OTH

AF:

0.149

Alfa

AF:

0.159

Hom.:

1135

Bravo

AF:

0.128

Asia WGS

AF:

0.125

AC:

435

AN:

3478

EpiCase

AF:

0.161

EpiControl

AF:

0.164

ClinVar

Significance: Benign

Submissions summary: Benign:7Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 22, 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	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 29, 2014	p.Thr623Thr in exon 11 of MYPN: This variant is not expected to have clinical si gnificance because it has been identified in 17% (1492/8600) of European America n chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.ed u/EVS/; dbSNP rs61854624). -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

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	-	- -

Dilated cardiomyopathy 1KK

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 12, 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

BayesDel_noAF

Benign

-0.72

CADD

Benign

4.1

DANN

Benign

0.28

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