rs7916821

Positions:

chr10-68174212-G-A

Variant summary

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

The NM_032578.4(MYPN):c.2120G>A(p.Ser707Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.462 in 1,613,710 control chromosomes in the GnomAD database, including 177,811 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.39 ( 12850 hom., cov: 30)

Exomes 𝑓: 0.47 ( 164961 hom. )

Consequence

MYPN
NM_032578.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10O:1

Conservation

PhyloP100: 0.843

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=0.0013567209).

BP6

Variant 10-68174212-G-A is Benign according to our data. Variant chr10-68174212-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 31798.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-68174212-G-A is described in Lovd as [Benign]. Variant chr10-68174212-G-A is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.485 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.2120G>A	p.Ser707Asn	missense_variant	11/20	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.2120G>A	p.Ser707Asn	missense_variant	11/20	1	NM_032578.4	ENSP00000351790	P1	Q86TC9-1

Frequencies

GnomAD3 genomes

AF:

0.392

AC:

59434

AN:

151810

Hom.:

12852

Cov.:

show subpopulations

Gnomad AFR

AF:

0.212

Gnomad AMI

AF:

0.424

Gnomad AMR

AF:

0.417

Gnomad ASJ

AF:

0.318

Gnomad EAS

AF:

0.215

Gnomad SAS

AF:

0.424

Gnomad FIN

AF:

0.528

Gnomad MID

AF:

0.253

Gnomad NFE

AF:

0.489

Gnomad OTH

AF:

0.390

GnomAD3 exomes

AF:

0.426

AC:

107176

AN:

251470

Hom.:

24298

AF XY:

0.432

AC XY:

58726

AN XY:

135906

show subpopulations

Gnomad AFR exome

AF:

0.204

Gnomad AMR exome

AF:

0.417

Gnomad ASJ exome

AF:

0.329

Gnomad EAS exome

AF:

0.198

Gnomad SAS exome

AF:

0.427

Gnomad FIN exome

AF:

0.528

Gnomad NFE exome

AF:

0.487

Gnomad OTH exome

AF:

0.428

GnomAD4 exome

AF:

0.470

AC:

686512

AN:

1461782

Hom.:

164961

Cov.:

AF XY:

0.469

AC XY:

341410

AN XY:

727196

show subpopulations

Gnomad4 AFR exome

AF:

0.201

Gnomad4 AMR exome

AF:

0.415

Gnomad4 ASJ exome

AF:

0.326

Gnomad4 EAS exome

AF:

0.246

Gnomad4 SAS exome

AF:

0.432

Gnomad4 FIN exome

AF:

0.524

Gnomad4 NFE exome

AF:

0.494

Gnomad4 OTH exome

AF:

0.433

GnomAD4 genome

AF:

0.391

AC:

59468

AN:

151928

Hom.:

12850

Cov.:

AF XY:

0.391

AC XY:

29042

AN XY:

74208

show subpopulations

Gnomad4 AFR

AF:

0.212

Gnomad4 AMR

AF:

0.417

Gnomad4 ASJ

AF:

0.318

Gnomad4 EAS

AF:

0.215

Gnomad4 SAS

AF:

0.425

Gnomad4 FIN

AF:

0.528

Gnomad4 NFE

AF:

0.489

Gnomad4 OTH

AF:

0.390

Alfa

AF:

0.453

Hom.:

40090

Bravo

AF:

0.370

TwinsUK

AF:

0.497

AC:

1842

ALSPAC

AF:

0.485

AC:

1868

ESP6500AA

AF:

0.222

AC:

977

ESP6500EA

AF:

0.480

AC:

4126

ExAC

AF:

0.426

AC:

51700

Asia WGS

AF:

0.303

AC:

1053

AN:

3478

EpiCase

AF:

0.478

EpiControl

AF:

0.469

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 29, 2014	p.Ser707Asn in exon 12 of MYPN: This variant is not expected to have clinical si gnificance because it has been identified in 48% (4126/8600) of European America n chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.ed u/EVS/; dbSNP rs7916821). -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 04, 2023	- -
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	GeneDx	Nov 13, 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. -

Dilated cardiomyopathy 1KK

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 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	-	- -

MYPN-related myopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 16, 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

0.15

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.54

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.024

.;.;.;T

Eigen

Benign

-0.20

Eigen_PC

Benign

-0.052

FATHMM_MKL

Benign

0.40

LIST_S2

Benign

0.78

T;T;.;T

MetaRNN

Benign

0.0014

T;T;T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

1.6

L;.;L;.

MutationTaster

Benign

0.97

P;P;P

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.25

N;N;N;.

REVEL

Benign

0.097

Sift

Benign

0.27

T;T;T;.

Sift4G

Benign

0.31

T;T;T;T

Polyphen

0.026

B;B;B;.

Vest4

0.046

MPC

0.13

ClinPred

0.0042

GERP RS

4.7

Varity_R

0.070

gMVP

0.11

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