10-68121896-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP5

The NM_032578.4(MYPN):c.458A>G(p.Lys153Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000167 in 1,614,120 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K153N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: MYPN NM_032578.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2 O:1
• Conservation: PhyloP100: 8.58

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PP5: Variant 10-68121896-A-G is Pathogenic according to our data. Variant chr10-68121896-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 31812.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, not_provided=1, Likely_pathogenic=1}. Variant chr10-68121896-A-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYPN	NM_032578.4	c.458A>G	p.Lys153Arg	missense_variant	2/20	ENST00000358913.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYPN	ENST00000358913.10	c.458A>G	p.Lys153Arg	missense_variant	2/20	1	NM_032578.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152236 Hom.: 0 Cov.: 32

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: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000164 AC: 24 AN: 1461884 Hom.: 0 Cov.: 31 AF XY: 0.0000193 AC XY: 14 AN XY: 727244

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: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000198

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152236 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74380

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000158 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Dilated cardiomyopathy 1KK Uncertain:2

Uncertain significance, no assertion criteria provided	literature only	ClinVar Staff, National Center for Biotechnology Information (NCBI)	Jun 27, 2013	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Aug 17, 2023	This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 153 of the MYPN protein (p.Lys153Arg). This variant is present in population databases (rs199476401, gnomAD 0.02%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy or left ventricular non-compaction (PMID: 22286171, 33049752). ClinVar contains an entry for this variant (Variation ID: 31812). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on MYPN function (PMID: 22286171). 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. -

Primary dilated cardiomyopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

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

Oct 10, 2017

The patient had early onset dilated cardiomyopathy and LVNC presented at 12 years old and subjected to Htx at 14 y.o. No familial history of cardiac disorders was reported. -

not provided Other:1

not provided, no classification provided

curation

Leiden Muscular Dystrophy (MYPN)

Apr 27, 2012

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
Cadd	Uncertain	24
Dann	Uncertain	1.0
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.84	T;.;T
M_CAP	Benign	0.026	D
MetaRNN	Uncertain	0.46	T;T;T
MetaSVM	Benign	-0.37	T
MutationAssessor	Benign	1.8	L;L;L
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-1.2	N;N;N
REVEL	Uncertain	0.38
Sift	Benign	0.11	T;T;T
Sift4G	Benign	0.20	T;T;T
Polyphen		1.0	D;D;D
Vest4		0.62
MutPred		0.23		Loss of ubiquitination at K153 (P = 0.0071);Loss of ubiquitination at K153 (P = 0.0071);Loss of ubiquitination at K153 (P = 0.0071);
MVP		0.81
MPC		0.55
ClinPred		0.87	D
GERP RS		6.0
Varity_R		0.19
gMVP		0.47

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs199476401; hg19: chr10-69881653;