dbSNP rs138313730: MYPN:p.Leu1161Ile (chr10-68199563-C-A) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_032578.4(MYPN):c.3481C>A(p.Leu1161Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00101 in 1,607,316 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L1161L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0013 ( 4 hom., cov: 31)

Exomes 𝑓: 0.00098 ( 17 hom. )

Consequence

MYPN
NM_032578.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:16O:1

Conservation

PhyloP100: 5.03

Publications

9 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: ClinGen, Labcorp Genetics (formerly Invitae)
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: 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008320689).

BP6

Variant 10-68199563-C-A is Benign according to our data. Variant chr10-68199563-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 31819.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0013 (189/145522) while in subpopulation AMR AF = 0.00775 (111/14322). AF 95% confidence interval is 0.00658. There are 4 homozygotes in GnomAd4. There are 85 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 4 AD,AR gene

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	UniProt
MYPN	NM_032578.4	MANE Select	c.3481C>A	p.Leu1161Ile	missense	Exon 17 of 20	NP_115967.2	Q86TC9-1
MYPN	NM_001256267.2		c.3481C>A	p.Leu1161Ile	missense	Exon 18 of 21	NP_001243196.1	Q86TC9-1
MYPN	NM_001256268.2		c.2599C>A	p.Leu867Ile	missense	Exon 21 of 24	NP_001243197.1	A0A087WX60

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MYPN	ENST00000358913.10	TSL:1 MANE Select	c.3481C>A	p.Leu1161Ile	missense	Exon 17 of 20	ENSP00000351790.5	Q86TC9-1
MYPN	ENST00000540630.6	TSL:1	c.3535C>A	p.Leu1179Ile	missense	Exon 17 of 20	ENSP00000441668.3	A0A8J9ASZ5
MYPN	ENST00000613327.5	TSL:1	c.3481C>A	p.Leu1161Ile	missense	Exon 18 of 21	ENSP00000480757.2	Q86TC9-1

Frequencies

GnomAD3 genomes

AF:

0.00130

AC:

189

AN:

145398

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000824

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00769

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00535

Gnomad SAS

AF:

0.00112

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000199

Gnomad OTH

AF:

0.000505

GnomAD2 exomes

AF:

0.00381

AC:

957

AN:

251238

AF XY:

0.00305

show subpopulations

Gnomad AFR exome

AF:

0.000431

Gnomad AMR exome

AF:

0.0227

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00506

Gnomad FIN exome

AF:

0.000185

Gnomad NFE exome

AF:

0.000167

Gnomad OTH exome

AF:

0.00473

GnomAD4 exome

AF:

0.000977

AC:

1428

AN:

1461794

Hom.:

Cov.:

AF XY:

0.000887

AC XY:

645

AN XY:

727208

show subpopulations

African (AFR)

AF:

0.000358

AC:

AN:

33480

American (AMR)

AF:

0.0196

AC:

877

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00527

AC:

209

AN:

39696

South Asian (SAS)

AF:

0.000754

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.000318

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000182

AC:

202

AN:

1111930

Other (OTH)

AF:

0.000745

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

166

249

332

415

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

130

<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:

0.00130

AC:

189

AN:

145522

Hom.:

Cov.:

AF XY:

0.00120

AC XY:

AN XY:

70734

show subpopulations

African (AFR)

AF:

0.000822

AC:

AN:

40148

American (AMR)

AF:

0.00775

AC:

111

AN:

14322

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3426

East Asian (EAS)

AF:

0.00516

AC:

AN:

5038

South Asian (SAS)

AF:

0.00112

AC:

AN:

4456

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9684

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.000199

AC:

AN:

65278

Other (OTH)

AF:

0.000500

AC:

AN:

2002

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000963

Hom.:

Bravo

AF:

0.00254

Asia WGS

AF:

0.00318

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.000178

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Dilated cardiomyopathy 1KK (6)

not provided (7)

not specified (4)

Cardiovascular phenotype (1)

Primary dilated cardiomyopathy;C0018801:Heart failure;C0878544:Cardiomyopathy (1)

Primary familial dilated cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.088

BayesDel_noAF

Uncertain

0.12

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.090

Eigen

Pathogenic

0.77

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.94

MetaRNN

Benign

0.0083

MetaSVM

Uncertain

0.41

MutationAssessor

Benign

1.9

PhyloP100

5.0

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-1.7

REVEL

Pathogenic

0.71

Sift

Benign

0.047

Sift4G

Pathogenic

0.0

Varity_R

0.41

gMVP

0.37

Mutation Taster

=82/18

polymorphism

(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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

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

Computational scores

Splicing

Publications

Other links and lift over