rs199476414

chr10-68189065-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4 BS1_Supporting BS2

The NM_032578.4(MYPN):c.2864G>A(p.Arg955Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000107 in 1,614,012 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R955W) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: MYPN NM_032578.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:8 O:1
• Conservation: PhyloP100: 3.95

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.3837707).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.00011 (161/1461848) while in subpopulation NFE AF= 0.000134 (149/1111986). AF 95% confidence interval is 0.000116. There are 0 homozygotes in gnomad4_exome. There are 73 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYPN	NM_032578.4	c.2864G>A	p.Arg955Gln	missense_variant	13/20	ENST00000358913.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYPN	ENST00000358913.10	c.2864G>A	p.Arg955Gln	missense_variant	13/20	1	NM_032578.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000789 AC: 12 AN: 152164 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.0000882

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000558 AC: 14 AN: 250888 Hom.: 0 AF XY: 0.0000516 AC XY: 7 AN XY: 135552

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000706

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000110 AC: 161 AN: 1461848 Hom.: 0 Cov.: 30 AF XY: 0.000100 AC XY: 73 AN XY: 727224

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000134

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000789 AC: 12 AN: 152164 Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8 AN XY: 74328

Gnomad4 AFR AF: 0.0000965

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000135 Hom.: 0

Bravo AF: 0.0000907

ExAC AF: 0.0000576 AC: 7

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:5 Other:1

Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
not provided, no classification provided	curation	Leiden Muscular Dystrophy (MYPN)	Apr 27, 2012	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 14, 2023	Reported in patients with cardiomyopathy in published literature (Purejav et al., 2012; van Lint et al., 2019; Mazzarotto et al., 2020); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23861362, 31983221, 22286171, 30847666) -
Uncertain significance, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Dilated cardiomyopathy 1KK Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Aug 09, 2022	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 955 of the MYPN protein (p.Arg955Gln). This variant is present in population databases (rs199476414, gnomAD 0.01%). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 22286171, 31983221). ClinVar contains an entry for this variant (Variation ID: 31831). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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. -

Dilated cardiomyopathy 1KK;C4479186:MYPN-related myopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 20, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.27
Cadd	Pathogenic	29
Dann	Pathogenic	1.0
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.97	D;D;.;D
M_CAP	Uncertain	0.087	D
MetaRNN	Benign	0.38	T;T;T;T
MetaSVM	Benign	-0.46	T
MutationAssessor	Benign	1.1	L;.;L;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.4	N;N;N;.
REVEL	Benign	0.21
Sift	Uncertain	0.0060	D;D;D;.
Sift4G	Uncertain	0.010	D;D;D;D
Polyphen		1.0	D;D;D;.
Vest4		0.54
MVP		0.81
MPC		0.65
ClinPred		0.26	T
GERP RS		5.8
Varity_R		0.21
gMVP		0.43

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs199476414; hg19: chr10-69948822;