rs10823148

chr10-68166577-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_032578.4(MYPN):c.1884C>G(p.Phe628Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.483 in 1,613,842 control chromosomes in the GnomAD database, including 196,299 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.40 (13839 hom., cov: 31)
  • Exomes 𝑓: 0.49 (182460 hom.)
• Consequence: MYPN NM_032578.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9 O:1
• Conservation: PhyloP100: 1.71

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=3.222823E-4).
• BP6: Variant 10-68166577-C-G is Benign according to our data. Variant chr10-68166577-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 31804.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-68166577-C-G is described in Lovd as [Benign]. Variant chr10-68166577-C-G is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.513 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYPN	NM_032578.4	c.1884C>G	p.Phe628Leu	missense_variant	10/20	ENST00000358913.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYPN	ENST00000358913.10	c.1884C>G	p.Phe628Leu	missense_variant	10/20	1	NM_032578.4	P1

Frequencies

GnomAD3 genomes AF: 0.396 AC: 60141 AN: 151876 Hom.: 13846 Cov.: 31

Gnomad AFR AF: 0.167

Gnomad AMI AF: 0.532

Gnomad AMR AF: 0.434

Gnomad ASJ AF: 0.314

Gnomad EAS AF: 0.212

Gnomad SAS AF: 0.436

Gnomad FIN AF: 0.546

Gnomad MID AF: 0.259

Gnomad NFE AF: 0.518

Gnomad OTH AF: 0.391

GnomAD3 exomes AF: 0.440 AC: 110543 AN: 251344 Hom.: 26261 AF XY: 0.447 AC XY: 60687 AN XY: 135842

Gnomad AFR exome AF: 0.157

Gnomad AMR exome AF: 0.431

Gnomad ASJ exome AF: 0.328

Gnomad EAS exome AF: 0.195

Gnomad SAS exome AF: 0.436

Gnomad FIN exome AF: 0.544

Gnomad NFE exome AF: 0.513

Gnomad OTH exome AF: 0.443

GnomAD4 exome AF: 0.492 AC: 719955 AN: 1461848 Hom.: 182460 Cov.: 62 AF XY: 0.492 AC XY: 357766 AN XY: 727228

Gnomad4 AFR exome AF: 0.152

Gnomad4 AMR exome AF: 0.429

Gnomad4 ASJ exome AF: 0.326

Gnomad4 EAS exome AF: 0.239

Gnomad4 SAS exome AF: 0.443

Gnomad4 FIN exome AF: 0.540

Gnomad4 NFE exome AF: 0.523

Gnomad4 OTH exome AF: 0.448

GnomAD4 genome AF: 0.396 AC: 60150 AN: 151994 Hom.: 13839 Cov.: 31 AF XY: 0.396 AC XY: 29416 AN XY: 74304

Gnomad4 AFR AF: 0.167

Gnomad4 AMR AF: 0.433

Gnomad4 ASJ AF: 0.314

Gnomad4 EAS AF: 0.211

Gnomad4 SAS AF: 0.436

Gnomad4 FIN AF: 0.546

Gnomad4 NFE AF: 0.518

Gnomad4 OTH AF: 0.391

Alfa AF: 0.475 Hom.: 13584

Bravo AF: 0.372

TwinsUK AF: 0.530 AC: 1966

ALSPAC AF: 0.512 AC: 1973

ESP6500AA AF: 0.174 AC: 768

ESP6500EA AF: 0.510 AC: 4382

ExAC AF: 0.438 AC: 53153

Asia WGS AF: 0.298 AC: 1037 AN: 3478

EpiCase AF: 0.503

EpiControl AF: 0.493

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 04, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 29, 2014	p.Phe628Leu in exon 11 of MYPN: This variant is not expected to have clinical si gnificance because it has been identified in 51% (4382/8600) of European America n chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.ed u/EVS/; dbSNP rs10823148). -
Benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	May 13, 2016	- -
Benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 13, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Dilated cardiomyopathy 1KK Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

MYPN-related myopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 16, 2015

This alteration is classified as 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. -

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	Uncertain	0.55
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.49
Cadd	Benign	20
Dann	Benign	0.65
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.13
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.74	T;T;.;T
MetaRNN	Benign	0.00032	T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.83	L;.;L;.
MutationTaster	Benign	0.060	P;P;P
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.33	N;N;N;.
REVEL	Benign	0.058
Sift	Benign	0.56	T;T;T;.
Sift4G	Benign	0.72	T;T;T;T
Polyphen		0.0010	B;B;B;.
Vest4		0.12
MutPred		0.27		Loss of sheet (P = 0.0181);.;Loss of sheet (P = 0.0181);.;
MPC		0.16
ClinPred		0.0097	T
GERP RS		4.3
Varity_R		0.097
gMVP		0.26

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs10823148; hg19: chr10-69926334; COSMIC: COSV62734683; COSMIC: COSV62734683;