10-68122100-A-T

Position:

chr10-68122100-A-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBS1_SupportingBS2

The NM_032578.4(MYPN):c.662A>T(p.Asp221Val) variant causes a missense change. The variant allele was found at a frequency of 0.000121 in 1,614,238 control chromosomes in the GnomAD database, including 1 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 0.00018 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00011 ( 1 hom. )

Consequence

MYPN
NM_032578.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 4.29

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 -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.15552497).

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000177 (27/152360) while in subpopulation EAS AF= 0.00154 (8/5188). AF 95% confidence interval is 0.000767. There are 0 homozygotes in gnomad4. There are 16 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 27 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYPN	NM_032578.4 linkuse as main transcript	c.662A>T	p.Asp221Val	missense_variant	2/20	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.662A>T	p.Asp221Val	missense_variant	2/20	1	NM_032578.4	ENSP00000351790	P1	Q86TC9-1

Frequencies

GnomAD3 genomes

AF:

0.000177

AC:

AN:

152242

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:

0.00154

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.000376

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000147

AC:

AN:

251288

Hom.:

AF XY:

0.000191

AC XY:

AN XY:

135814

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.000457

Gnomad FIN exome

AF:

0.000231

Gnomad NFE exome

AF:

0.0000792

Gnomad OTH exome

AF:

0.000978

GnomAD4 exome

AF:

0.000115

AC:

168

AN:

1461878

Hom.:

Cov.:

AF XY:

0.000128

AC XY:

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.000348

Gnomad4 FIN exome

AF:

0.000187

Gnomad4 NFE exome

AF:

0.0000971

Gnomad4 OTH exome

AF:

0.000298

GnomAD4 genome

AF:

0.000177

AC:

AN:

152360

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74508

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00154

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.000376

Gnomad4 NFE

AF:

0.000162

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000141

Hom.:

Bravo

AF:

0.0000718

ExAC

AF:

0.000189

AC:

Asia WGS

AF:

0.00433

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 16, 2020	This variant is associated with the following publications: (PMID: 28831623, 27662471, 26350513) -
Uncertain significance, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -

Dilated cardiomyopathy 1KK

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 13, 2022

This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 221 of the MYPN protein (p.Asp221Val). This variant is present in population databases (rs185841477, gnomAD 0.05%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with sudden unexpected death in infancy (SUDI) (PMID: 26350513). ClinVar contains an entry for this variant (Variation ID: 191748). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 29, 2022

The p.D221V variant (also known as c.662A>T), located in coding exon 1 of the MYPN gene, results from an A to T substitution at nucleotide position 662. The aspartic acid at codon 221 is replaced by valine, an amino acid with highly dissimilar properties. This variant has been detected in individuals and cohorts with various phenotypes including coronary heart disease, ventricular arrhythmia, dilated cardiomyopathy, sudden unexplained death, and restrictive cardiomyopathy; however, details were limited and variants in other cardiac-related genes were detected in some cases (Kostareva A et al. PLoS One Sep;11:e0163362; Hertz CL et al. Eur J Hum Genet, 2016 06;24:817-22; Hertz CL et al. Eur J Hum Genet, 2016 06;24:817-22; van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309; Kars ME et al. Proc Natl Acad Sci U S A, 2021 09;118; Guelly C et al. PeerJ, 2021 Jan;9:e10711). This variant has also been detected in an exome cohort; however, details were limited (Ng D et al. Circ Cardiovasc Genet. 2013 Aug;6(4):337-46). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.50

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.14

CADD

Uncertain

DANN

Uncertain

0.98

Eigen

Uncertain

0.38

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.85

D;.;D

M_CAP

Benign

0.048

MetaRNN

Benign

0.16

T;T;T

MetaSVM

Benign

-0.70

MutationAssessor

Uncertain

2.1

M;M;M

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-0.98

N;N;N

REVEL

Benign

0.12

Sift

Benign

0.061

T;T;T

Sift4G

Uncertain

0.058

T;T;D

Polyphen

0.97

D;D;D

Vest4

0.67

MVP

0.74

MPC

0.20

ClinPred

0.099

GERP RS

5.7

Varity_R

0.18

gMVP

0.40

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