rs61854624

Positions:

• chr10-68166562-C-A
• chr10-68166562-C-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_032578.4(MYPN):​c.1869C>A​(p.Thr623=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.158 in 1,613,976 control chromosomes in the GnomAD database, including 21,862 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1677 hom., cov: 31)
  • Exomes 𝑓: 0.16 (20185 hom.)
• Consequence: MYPN NM_032578.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6 O:1
• Conservation: PhyloP100: 0.0800

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 10-68166562-C-A is Benign according to our data. Variant chr10-68166562-C-A is described in ClinVar as [Benign]. Clinvar id is 31803.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-68166562-C-A is described in Lovd as [Benign]. Variant chr10-68166562-C-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.08 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.179 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYPN	NM_032578.4	c.1869C>A	p.Thr623=	synonymous_variant	10/20	ENST00000358913.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYPN	ENST00000358913.10	c.1869C>A	p.Thr623=	synonymous_variant	10/20	1	NM_032578.4	P1

Frequencies

GnomAD3 genomes AF: 0.129 AC: 19639 AN: 152028 Hom.: 1672 Cov.: 31

Gnomad AFR AF: 0.0304

Gnomad AMI AF: 0.127

Gnomad AMR AF: 0.184

Gnomad ASJ AF: 0.304

Gnomad EAS AF: 0.0926

Gnomad SAS AF: 0.150

Gnomad FIN AF: 0.189

Gnomad MID AF: 0.199

Gnomad NFE AF: 0.159

Gnomad OTH AF: 0.150

GnomAD3 exomes AF: 0.165 AC: 41580 AN: 251312 Hom.: 3966 AF XY: 0.165 AC XY: 22413 AN XY: 135824

Gnomad AFR exome AF: 0.0295

Gnomad AMR exome AF: 0.238

Gnomad ASJ exome AF: 0.291

Gnomad EAS exome AF: 0.0913

Gnomad SAS exome AF: 0.158

Gnomad FIN exome AF: 0.184

Gnomad NFE exome AF: 0.162

Gnomad OTH exome AF: 0.177

GnomAD4 exome AF: 0.161 AC: 234964 AN: 1461830 Hom.: 20185 Cov.: 77 AF XY: 0.161 AC XY: 117159 AN XY: 727212

Gnomad4 AFR exome AF: 0.0257

Gnomad4 AMR exome AF: 0.237

Gnomad4 ASJ exome AF: 0.294

Gnomad4 EAS exome AF: 0.0926

Gnomad4 SAS exome AF: 0.159

Gnomad4 FIN exome AF: 0.184

Gnomad4 NFE exome AF: 0.160

Gnomad4 OTH exome AF: 0.156

GnomAD4 genome AF: 0.129 AC: 19660 AN: 152146 Hom.: 1677 Cov.: 31 AF XY: 0.132 AC XY: 9834 AN XY: 74364

Gnomad4 AFR AF: 0.0303

Gnomad4 AMR AF: 0.185

Gnomad4 ASJ AF: 0.304

Gnomad4 EAS AF: 0.0923

Gnomad4 SAS AF: 0.152

Gnomad4 FIN AF: 0.189

Gnomad4 NFE AF: 0.159

Gnomad4 OTH AF: 0.149

Alfa AF: 0.159 Hom.: 1135

Bravo AF: 0.128

Asia WGS AF: 0.125 AC: 435 AN: 3478

EpiCase AF: 0.161

EpiControl AF: 0.164

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	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 29, 2014	p.Thr623Thr in exon 11 of MYPN: This variant is not expected to have clinical si gnificance because it has been identified in 17% (1492/8600) of European America n chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.ed u/EVS/; dbSNP rs61854624). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 22, 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, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Dilated cardiomyopathy 1KK Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 12, 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
BayesDel_noAF	Benign	-0.72
CADD	Benign	4.1
DANN	Benign	0.28

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: rs61854624; hg19: chr10-69926319;