rs11596653

Positions:

• chr10-68148400-T-C
• chr10-68148400-T-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.1178T>C​(p.Val393Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0316 in 1,613,918 control chromosomes in the GnomAD database, including 4,645 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (2326 hom., cov: 32)
  • Exomes 𝑓: 0.024 (2319 hom.)
• Consequence: MYPN NM_032578.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6 O:1
• Conservation: PhyloP100: 0.416

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]

LOC107984240 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0033382177).
• BP6: Variant 10-68148400-T-C is Benign according to our data. Variant chr10-68148400-T-C is described in ClinVar as [Benign]. Clinvar id is 31793.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-68148400-T-C is described in Lovd as [Benign]. Variant chr10-68148400-T-C is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.321 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYPN	NM_032578.4	c.1178T>C	p.Val393Ala	missense_variant	5/20	ENST00000358913.10
LOC107984240	XR_001747479.2	n.206-1682A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYPN	ENST00000358913.10	c.1178T>C	p.Val393Ala	missense_variant	5/20	1	NM_032578.4	P1

Frequencies

GnomAD3 genomes AF: 0.104 AC: 15775 AN: 152070 Hom.: 2315 Cov.: 32

Gnomad AFR AF: 0.326

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0467

Gnomad ASJ AF: 0.00951

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0274

Gnomad FIN AF: 0.0140

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.0158

Gnomad OTH AF: 0.0894

GnomAD3 exomes AF: 0.0390 AC: 9797 AN: 251430 Hom.: 994 AF XY: 0.0342 AC XY: 4648 AN XY: 135888

Gnomad AFR exome AF: 0.333

Gnomad AMR exome AF: 0.0264

Gnomad ASJ exome AF: 0.00963

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0359

Gnomad FIN exome AF: 0.0127

Gnomad NFE exome AF: 0.0159

Gnomad OTH exome AF: 0.0316

GnomAD4 exome AF: 0.0240 AC: 35104 AN: 1461730 Hom.: 2319 Cov.: 31 AF XY: 0.0237 AC XY: 17240 AN XY: 727166

Gnomad4 AFR exome AF: 0.336

Gnomad4 AMR exome AF: 0.0283

Gnomad4 ASJ exome AF: 0.00853

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0365

Gnomad4 FIN exome AF: 0.0128

Gnomad4 NFE exome AF: 0.0142

Gnomad4 OTH exome AF: 0.0398

GnomAD4 genome AF: 0.104 AC: 15823 AN: 152188 Hom.: 2326 Cov.: 32 AF XY: 0.101 AC XY: 7481 AN XY: 74422

Gnomad4 AFR AF: 0.326

Gnomad4 AMR AF: 0.0466

Gnomad4 ASJ AF: 0.00951

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0276

Gnomad4 FIN AF: 0.0140

Gnomad4 NFE AF: 0.0158

Gnomad4 OTH AF: 0.0885

Alfa AF: 0.0366 Hom.: 700

Bravo AF: 0.116

TwinsUK AF: 0.0138 AC: 51

ALSPAC AF: 0.0140 AC: 54

ESP6500AA AF: 0.332 AC: 1464

ESP6500EA AF: 0.0147 AC: 126

ExAC AF: 0.0452 AC: 5491

Asia WGS AF: 0.0360 AC: 125 AN: 3478

EpiCase AF: 0.0183

EpiControl AF: 0.0164

ClinVar

Significance: Benign

Submissions summary: Benign:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 13, 2015	p.Val393Ala in exon 6 of MYPN: This variant is not expected to have clinical sig nificance because it has been identified in 33.2% (1464/4406) of African America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs11596653). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 10, 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. -
Benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	May 13, 2016	- -

Dilated cardiomyopathy 1KK Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 19, 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	Benign	0.11
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	15
DANN	Benign	0.93
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.046	N
LIST_S2	Benign	0.046	T;T;.;T;T
MetaRNN	Benign	0.0033	T;T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-0.20	N;.;N;.;N
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.090	N;N;N;.;N
REVEL	Benign	0.037
Sift	Benign	0.45	T;T;T;.;T
Sift4G	Benign	0.40	T;T;T;T;T
Polyphen		0.0	B;B;B;.;B
Vest4		0.049
MPC		0.16
ClinPred		0.0021	T
GERP RS		2.5
Varity_R		0.034
gMVP		0.16

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: rs11596653; hg19: chr10-69908157;