10-68122240-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_032578.4(MYPN):c.802C>T(p.Pro268Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000206 in 1,612,736 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00030 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00020 ( 2 hom. )

Consequence

MYPN
NM_032578.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

Conservation

PhyloP100: 5.64

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.029155672).

BP6

Variant 10-68122240-C-T is Benign according to our data. Variant chr10-68122240-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 444869.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2}.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000302 (46/152204) while in subpopulation SAS AF= 0.000414 (2/4834). AF 95% confidence interval is 0.000112. There are 0 homozygotes in gnomad4. There are 33 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 46 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYPN	NM_032578.4 link	c.802C>T	p.Pro268Ser	missense_variant	Exon 2 of 20	ENST00000358913.10	NP_115967.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYPN	ENST00000358913.10 link	c.802C>T	p.Pro268Ser	missense_variant	Exon 2 of 20	1	NM_032578.4	ENSP00000351790.5		Q86TC9-1

Frequencies

GnomAD3 genomes

AF:

0.000302

AC:

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00292

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000441

AC:

110

AN:

249638

Hom.:

AF XY:

0.000467

AC XY:

AN XY:

134900

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000396

Gnomad FIN exome

AF:

0.00367

Gnomad NFE exome

AF:

0.000124

Gnomad OTH exome

AF:

0.000823

GnomAD4 exome

AF:

0.000196

AC:

286

AN:

1460532

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

156

AN XY:

726538

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000407

Gnomad4 FIN exome

AF:

0.00352

Gnomad4 NFE exome

AF:

0.0000513

Gnomad4 OTH exome

AF:

0.0000995

GnomAD4 genome

AF:

0.000302

AC:

AN:

152204

Hom.:

Cov.:

AF XY:

0.000444

AC XY:

AN XY:

74344

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00292

Gnomad4 NFE

AF:

0.000191

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000579

Hom.:

Bravo

AF:

0.0000453

ExAC

AF:

0.000296

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Restrictive cardiomyopathy

Uncertain:1

Institute Of Molecular Biology And Genetics, Federal Almazov National Medical Research Centre

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

This variant is detected in a patient with restrictive cardiomyopathy presented at 3 years old in combination with MYH6 variant chr 14:23858646 g>c -

not provided

Uncertain:1

Sep 10, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified in a patient with HCM in published literature; however, this patient harbored additional cardiogenetic variants (PMID: 30775854); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30775854) -

Dilated cardiomyopathy 1KK

Benign:1

Dec 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype

Benign:1

May 23, 2023

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely 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

0.31

BayesDel_addAF

Benign

-0.072

BayesDel_noAF

Uncertain

-0.020

CADD

Uncertain

DANN

Pathogenic

1.0

Eigen

Pathogenic

0.73

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.85

T;.;T

M_CAP

Benign

0.040

MetaRNN

Benign

0.029

T;T;T

MetaSVM

Uncertain

-0.10

MutationAssessor

Uncertain

2.2

M;M;M

PrimateAI

Uncertain

0.65

PROVEAN

Uncertain

-3.1

D;D;D

REVEL

Uncertain

0.53

Sift

Uncertain

0.0050

D;D;D

Sift4G

Benign

0.091

T;T;D

Polyphen

1.0

D;D;D

Vest4

0.63

MutPred

0.54

Loss of catalytic residue at P268 (P = 0.0034);Loss of catalytic residue at P268 (P = 0.0034);Loss of catalytic residue at P268 (P = 0.0034);

MVP

0.87

MPC

0.61

ClinPred

0.15

GERP RS

5.7

Varity_R

0.25

gMVP

0.65

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

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