rs11596653

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.1178T>C(p.Val393Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0316 in 1,613,918 control chromosomes in the GnomAD database, including 4,645 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.10 ( 2326 hom., cov: 32)

Exomes 𝑓: 0.024 ( 2319 hom. )

Consequence

MYPN
NM_032578.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.416

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:

LOC107984240 (HGNC:):

LOC107984240 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=0.0033382177).

BP6

Variant 10-68148400-T-C is Benign according to our data. Variant chr10-68148400-T-C is described in ClinVar as [Benign]. Clinvar id is 31793.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-68148400-T-C is described in Lovd as [Benign]. Variant chr10-68148400-T-C is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.321 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.1178T>C	p.Val393Ala	missense_variant	5/20	ENST00000358913.10	NP_115967.2
LOC107984240	XR_001747479.2 linkuse as main transcript	n.206-1682A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYPN	ENST00000358913.10 linkuse as main transcript	c.1178T>C	p.Val393Ala	missense_variant	5/20	1	NM_032578.4	ENSP00000351790	P1	Q86TC9-1

Frequencies

GnomAD3 genomes

AF:

0.104

AC:

15775

AN:

152070

Hom.:

2315

Cov.:

show subpopulations

Gnomad AFR

AF:

0.326

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0467

Gnomad ASJ

AF:

0.00951

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0274

Gnomad FIN

AF:

0.0140

Gnomad MID

AF:

0.0665

Gnomad NFE

AF:

0.0158

Gnomad OTH

AF:

0.0894

GnomAD3 exomes

AF:

0.0390

AC:

9797

AN:

251430

Hom.:

994

AF XY:

0.0342

AC XY:

4648

AN XY:

135888

show subpopulations

Gnomad AFR exome

AF:

0.333

Gnomad AMR exome

AF:

0.0264

Gnomad ASJ exome

AF:

0.00963

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.0359

Gnomad FIN exome

AF:

0.0127

Gnomad NFE exome

AF:

0.0159

Gnomad OTH exome

AF:

0.0316

GnomAD4 exome

AF:

0.0240

AC:

35104

AN:

1461730

Hom.:

2319

Cov.:

AF XY:

0.0237

AC XY:

17240

AN XY:

727166

show subpopulations

Gnomad4 AFR exome

AF:

0.336

Gnomad4 AMR exome

AF:

0.0283

Gnomad4 ASJ exome

AF:

0.00853

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.0365

Gnomad4 FIN exome

AF:

0.0128

Gnomad4 NFE exome

AF:

0.0142

Gnomad4 OTH exome

AF:

0.0398

GnomAD4 genome

AF:

0.104

AC:

15823

AN:

152188

Hom.:

2326

Cov.:

AF XY:

0.101

AC XY:

7481

AN XY:

74422

show subpopulations

Gnomad4 AFR

AF:

0.326

Gnomad4 AMR

AF:

0.0466

Gnomad4 ASJ

AF:

0.00951

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0276

Gnomad4 FIN

AF:

0.0140

Gnomad4 NFE

AF:

0.0158

Gnomad4 OTH

AF:

0.0885

Alfa

AF:

0.0366

Hom.:

700

Bravo

AF:

0.116

TwinsUK

AF:

0.0138

AC:

ALSPAC

AF:

0.0140

AC:

ESP6500AA

AF:

0.332

AC:

1464

ESP6500EA

AF:

0.0147

AC:

126

ExAC

AF:

0.0452

AC:

5491

Asia WGS

AF:

0.0360

AC:

125

AN:

3478

EpiCase

AF:

0.0183

EpiControl

AF:

0.0164

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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 13, 2015	p.Val393Ala in exon 6 of MYPN: This variant is not expected to have clinical sig nificance because it has been identified in 33.2% (1464/4406) of African America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs11596653). -
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	May 13, 2016	- -
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. -

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

Jan 31, 2024

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 19, 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

0.11

BayesDel_addAF

Benign

-0.72

BayesDel_noAF

Benign

-0.67

CADD

Benign

DANN

Benign

0.93

DEOGEN2

Benign

0.024

.;.;.;T;.

Eigen

Benign

-0.70

Eigen_PC

Benign

-0.48

FATHMM_MKL

Benign

0.046

LIST_S2

Benign

0.046

T;T;.;T;T

MetaRNN

Benign

0.0033

T;T;T;T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

-0.20

N;.;N;.;N

MutationTaster

Benign

1.0

P;P;P;P

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.090

N;N;N;.;N

REVEL

Benign

0.037

Sift

Benign

0.45

T;T;T;.;T

Sift4G

Benign

0.40

T;T;T;T;T

Polyphen

0.0

B;B;B;.;B

Vest4

0.049

MPC

0.16

ClinPred

0.0021

GERP RS

2.5

Varity_R

0.034

gMVP

0.16

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