Genetic Variant MYPN:p.Pro625Pro (chr10-68166568-C-T) – 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.1875C>T(p.Pro625Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.177 in 1,613,890 control chromosomes in the GnomAD database, including 26,627 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P625P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.17 ( 2468 hom., cov: 31)

Exomes 𝑓: 0.18 ( 24159 hom. )

Consequence

MYPN
NM_032578.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -2.56

Publications

13 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=-0.76).

BP6

Variant 10-68166568-C-T is Benign according to our data. Variant chr10-68166568-C-T is described in ClinVar as Benign. ClinVar VariationId is 31796.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.56 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.197 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.1875C>T	p.Pro625Pro	synonymous	Exon 10 of 20	NP_115967.2
MYPN	NM_001256267.2		c.1875C>T	p.Pro625Pro	synonymous	Exon 11 of 21	NP_001243196.1
MYPN	NM_001256268.2		c.993C>T	p.Pro331Pro	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.1875C>T	p.Pro625Pro	synonymous	Exon 10 of 20	ENSP00000351790.5
MYPN	ENST00000540630.6	TSL:1	c.1929C>T	p.Pro643Pro	synonymous	Exon 10 of 20	ENSP00000441668.3
MYPN	ENST00000613327.5	TSL:1	c.1875C>T	p.Pro625Pro	synonymous	Exon 11 of 21	ENSP00000480757.2

Frequencies

GnomAD3 genomes

AF:

0.174

AC:

26371

AN:

151958

Hom.:

2457

Cov.:

show subpopulations

Gnomad AFR

AF:

0.153

Gnomad AMI

AF:

0.127

Gnomad AMR

AF:

0.202

Gnomad ASJ

AF:

0.323

Gnomad EAS

AF:

0.0923

Gnomad SAS

AF:

0.177

Gnomad FIN

AF:

0.200

Gnomad MID

AF:

0.241

Gnomad NFE

AF:

0.173

Gnomad OTH

AF:

0.187

GnomAD2 exomes

AF:

0.188

AC:

47270

AN:

251328

AF XY:

0.187

show subpopulations

Gnomad AFR exome

AF:

0.154

Gnomad AMR exome

AF:

0.250

Gnomad ASJ exome

AF:

0.309

Gnomad EAS exome

AF:

0.0915

Gnomad FIN exome

AF:

0.195

Gnomad NFE exome

AF:

0.176

Gnomad OTH exome

AF:

0.196

GnomAD4 exome

AF:

0.177

AC:

259468

AN:

1461812

Hom.:

24159

Cov.:

AF XY:

0.178

AC XY:

129645

AN XY:

727212

show subpopulations

African (AFR)

AF:

0.157

AC:

5253

AN:

33480

American (AMR)

AF:

0.250

AC:

11162

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.312

AC:

8160

AN:

26136

East Asian (EAS)

AF:

0.0927

AC:

3680

AN:

39696

South Asian (SAS)

AF:

0.193

AC:

16663

AN:

86254

European-Finnish (FIN)

AF:

0.196

AC:

10487

AN:

53416

Middle Eastern (MID)

AF:

0.224

AC:

1293

AN:

5768

European-Non Finnish (NFE)

AF:

0.173

AC:

191934

AN:

1111950

Other (OTH)

AF:

0.179

AC:

10836

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

12520

25040

37560

50080

62600

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6804

13608

20412

27216

34020

<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:

0.174

AC:

26413

AN:

152078

Hom.:

2468

Cov.:

AF XY:

0.175

AC XY:

13002

AN XY:

74330

show subpopulations

African (AFR)

AF:

0.153

AC:

6364

AN:

41492

American (AMR)

AF:

0.203

AC:

3100

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.323

AC:

1120

AN:

3470

East Asian (EAS)

AF:

0.0923

AC:

478

AN:

5180

South Asian (SAS)

AF:

0.178

AC:

857

AN:

4808

European-Finnish (FIN)

AF:

0.200

AC:

2117

AN:

10564

Middle Eastern (MID)

AF:

0.255

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.173

AC:

11792

AN:

67980

Other (OTH)

AF:

0.186

AC:

394

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1091

2182

3273

4364

5455

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

284

568

852

1136

1420

<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:

0.167

Hom.:

1037

Bravo

AF:

0.177

Asia WGS

AF:

0.141

AC:

491

AN:

3478

EpiCase

AF:

0.179

EpiControl

AF:

0.179

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (4)

Cardiovascular phenotype (1)

Dilated cardiomyopathy 1KK (1)

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.76

CADD

Benign

0.24

(source)

DANN

Benign

0.32

PhyloP100

-2.6

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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

Computational scores

Splicing

Publications

Other links and lift over