Genetic Variant MYPN:p.Ser549Ser (chr10-68166340-T-C) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_032578.4(MYPN):c.1647T>C(p.Ser549Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.662 in 1,613,676 control chromosomes in the GnomAD database, including 361,854 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.58 ( 27464 hom., cov: 30)

Exomes 𝑓: 0.67 ( 334390 hom. )

Consequence

MYPN
NM_032578.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8O:1

Conservation

PhyloP100: 0.225

Publications

22 publications found

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 Gene-Disease associations (from GenCC):

MYPN-related myopathy
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen
cap myopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
childhood-onset nemaline myopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
familial isolated dilated cardiomyopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
familial isolated restrictive cardiomyopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
dilated cardiomyopathy
Inheritance: AD Classification: LIMITED Submitted by: ClinGen
dilated cardiomyopathy 1KK
Inheritance: AD Classification: LIMITED Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae)
hypertrophic cardiomyopathy
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

MYPN links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

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

BP6

Variant 10-68166340-T-C is Benign according to our data. Variant chr10-68166340-T-C is described in ClinVar as Benign. ClinVar VariationId is 31795.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.225 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.686 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032578.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MYPN	NM_032578.4	MANE Select	c.1647T>C	p.Ser549Ser	synonymous	Exon 10 of 20	NP_115967.2
MYPN	NM_001256267.2		c.1647T>C	p.Ser549Ser	synonymous	Exon 11 of 21	NP_001243196.1
MYPN	NM_001256268.2		c.765T>C	p.Ser255Ser	synonymous	Exon 14 of 24	NP_001243197.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MYPN	ENST00000358913.10	TSL:1 MANE Select	c.1647T>C	p.Ser549Ser	synonymous	Exon 10 of 20	ENSP00000351790.5
MYPN	ENST00000540630.6	TSL:1	c.1701T>C	p.Ser567Ser	synonymous	Exon 10 of 20	ENSP00000441668.3
MYPN	ENST00000613327.5	TSL:1	c.1647T>C	p.Ser549Ser	synonymous	Exon 11 of 21	ENSP00000480757.2

Frequencies

GnomAD3 genomes

AF:

0.578

AC:

87767

AN:

151750

Hom.:

27445

Cov.:

show subpopulations

Gnomad AFR

AF:

0.350

Gnomad AMI

AF:

0.657

Gnomad AMR

AF:

0.639

Gnomad ASJ

AF:

0.637

Gnomad EAS

AF:

0.304

Gnomad SAS

AF:

0.614

Gnomad FIN

AF:

0.747

Gnomad MID

AF:

0.503

Gnomad NFE

AF:

0.692

Gnomad OTH

AF:

0.586

GnomAD2 exomes

AF:

0.631

AC:

158506

AN:

251378

AF XY:

0.636

show subpopulations

Gnomad AFR exome

AF:

0.341

Gnomad AMR exome

AF:

0.683

Gnomad ASJ exome

AF:

0.637

Gnomad EAS exome

AF:

0.287

Gnomad FIN exome

AF:

0.739

Gnomad NFE exome

AF:

0.690

Gnomad OTH exome

AF:

0.640

GnomAD4 exome

AF:

0.671

AC:

980659

AN:

1461808

Hom.:

334390

Cov.:

AF XY:

0.671

AC XY:

487929

AN XY:

727204

show subpopulations

African (AFR)

AF:

0.338

AC:

11307

AN:

33480

American (AMR)

AF:

0.680

AC:

30419

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.638

AC:

16669

AN:

26136

East Asian (EAS)

AF:

0.332

AC:

13190

AN:

39692

South Asian (SAS)

AF:

0.636

AC:

54865

AN:

86258

European-Finnish (FIN)

AF:

0.737

AC:

39355

AN:

53420

Middle Eastern (MID)

AF:

0.568

AC:

3279

AN:

5768

European-Non Finnish (NFE)

AF:

0.696

AC:

773561

AN:

1111936

Other (OTH)

AF:

0.629

AC:

38014

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

19322

38644

57965

77287

96609

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19372

38744

58116

77488

96860

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.578

AC:

87820

AN:

151868

Hom.:

27464

Cov.:

AF XY:

0.580

AC XY:

43008

AN XY:

74194

show subpopulations

African (AFR)

AF:

0.350

AC:

14470

AN:

41390

American (AMR)

AF:

0.640

AC:

9763

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.637

AC:

2210

AN:

3470

East Asian (EAS)

AF:

0.304

AC:

1561

AN:

5138

South Asian (SAS)

AF:

0.616

AC:

2957

AN:

4800

European-Finnish (FIN)

AF:

0.747

AC:

7882

AN:

10546

Middle Eastern (MID)

AF:

0.497

AC:

145

AN:

292

European-Non Finnish (NFE)

AF:

0.692

AC:

47006

AN:

67960

Other (OTH)

AF:

0.584

AC:

1229

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1686

3373

5059

6746

8432

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

724

1448

2172

2896

3620

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.648

Hom.:

51587

Bravo

AF:

0.558

Asia WGS

AF:

0.446

AC:

1551

AN:

3478

EpiCase

AF:

0.682

EpiControl

AF:

0.674

ClinVar

Significance: Benign

Submissions summary: Benign:8Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Nov 22, 2013

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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.

May 13, 2016

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Oct 29, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Ser549Ser in exon 11 of MYPN: This variant is not expected to have clinical si gnificance because it has been identified in 70% (5986/8600) of European America n chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.ed u/EVS/; dbSNP rs2673794).

Dilated cardiomyopathy 1KK

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:1Other:1

Apr 27, 2012

Leiden Muscular Dystrophy (MYPN)

Significance:not provided

Review Status:no classification provided

Collection Method:curation

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

MYPN-related myopathy

Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Cardiovascular phenotype

Benign:1

Jun 12, 2015

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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 v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.64

CADD

Benign

7.5

(source)

DANN

Benign

0.56

PhyloP100

0.23

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over