NM_032578.4:c.2163C>A

Variant names:

• chr10-68174255-C-A
• rs71584491
• NM_032578.4:c.2163C>A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_032578.4(MYPN):​c.2163C>A​(p.Ala721Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0185 in 1,613,986 control chromosomes in the GnomAD database, including 761 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.041 (303 hom., cov: 31)
  • Exomes 𝑓: 0.016 (458 hom.)
• Consequence: MYPN NM_032578.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9 O:1
• Conservation: PhyloP100: 0.687

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.28).
• BP6: Variant 10-68174255-C-A is Benign according to our data. Variant chr10-68174255-C-A is described in ClinVar as [Benign]. Clinvar id is 31806.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-68174255-C-A is described in Lovd as [Benign]. Variant chr10-68174255-C-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.687 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.107 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYPN	NM_032578.4	c.2163C>A	p.Ala721Ala	synonymous_variant	Exon 11 of 20	ENST00000358913.10	NP_115967.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYPN	ENST00000358913.10	c.2163C>A	p.Ala721Ala	synonymous_variant	Exon 11 of 20	1	NM_032578.4	ENSP00000351790.5

Frequencies

GnomAD3 genomes AF: 0.0403 AC: 6132 AN: 151982 Hom.: 299 Cov.: 31

Gnomad AFR AF: 0.109

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0193

Gnomad ASJ AF: 0.0188

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0261

Gnomad FIN AF: 0.0112

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0139

Gnomad OTH AF: 0.0354

GnomAD3 exomes AF: 0.0217 AC: 5445 AN: 251444 Hom.: 141 AF XY: 0.0212 AC XY: 2887 AN XY: 135892

Gnomad AFR exome AF: 0.113

Gnomad AMR exome AF: 0.0125

Gnomad ASJ exome AF: 0.0189

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0329

Gnomad FIN exome AF: 0.0111

Gnomad NFE exome AF: 0.0142

Gnomad OTH exome AF: 0.0200

GnomAD4 exome AF: 0.0163 AC: 23776 AN: 1461886 Hom.: 458 Cov.: 75 AF XY: 0.0167 AC XY: 12127 AN XY: 727246

Gnomad4 AFR exome AF: 0.118

Gnomad4 AMR exome AF: 0.0135

Gnomad4 ASJ exome AF: 0.0182

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0332

Gnomad4 FIN exome AF: 0.0115

Gnomad4 NFE exome AF: 0.0123

Gnomad4 OTH exome AF: 0.0222

GnomAD4 genome AF: 0.0405 AC: 6162 AN: 152100 Hom.: 303 Cov.: 31 AF XY: 0.0396 AC XY: 2944 AN XY: 74366

Gnomad4 AFR AF: 0.109

Gnomad4 AMR AF: 0.0192

Gnomad4 ASJ AF: 0.0188

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0263

Gnomad4 FIN AF: 0.0112

Gnomad4 NFE AF: 0.0139

Gnomad4 OTH AF: 0.0350

Alfa AF: 0.0290 Hom.: 62

Bravo AF: 0.0445

Asia WGS AF: 0.0170 AC: 60 AN: 3478

EpiCase AF: 0.0172

EpiControl AF: 0.0146

ClinVar

Significance: Benign

Submissions summary: Benign:9 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 17, 2013

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

May 13, 2016

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 17, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Ala721Ala in exon 12 of MYPN: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue and is not located wi thin the splice consensus sequence. It has been identified in 10.4% (458/4406) o f African American chromosomes from a broad population by the NHLBI Exome Sequen cing Project (http://evs.gs.washington.edu/EVS; dbSNP rs71584491). -

not provided Benign:1 Other:1

Apr 27, 2012

Leiden Muscular Dystrophy (MYPN)

Significance: not provided

Review Status: no classification provided

Collection Method: curation

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Dilated cardiomyopathy 1KK Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

Jun 19, 2015

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.28
CADD	Benign	9.6
DANN	Benign	0.78

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

Other links and lift over

dbSNP: rs71584491; hg19: chr10-69934012;