rs7916821

chr10-68174212-G-A

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.2120G>A(p.Ser707Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.462 in 1,613,710 control chromosomes in the GnomAD database, including 177,811 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 0.39 (12850 hom., cov: 30)
  • Exomes 𝑓: 0.47 (164961 hom.)
• Consequence: MYPN NM_032578.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9 O:1
• Conservation: PhyloP100: 0.843

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=0.0013567209).
• BP6: Variant 10-68174212-G-A is Benign according to our data. Variant chr10-68174212-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 31798.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-68174212-G-A is described in Lovd as [Benign]. Variant chr10-68174212-G-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.485 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYPN	NM_032578.4	c.2120G>A	p.Ser707Asn	missense_variant	11/20	ENST00000358913.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYPN	ENST00000358913.10	c.2120G>A	p.Ser707Asn	missense_variant	11/20	1	NM_032578.4	P1

Frequencies

GnomAD3 genomes AF: 0.392 AC: 59434 AN: 151810 Hom.: 12852 Cov.: 30

Gnomad AFR AF: 0.212

Gnomad AMI AF: 0.424

Gnomad AMR AF: 0.417

Gnomad ASJ AF: 0.318

Gnomad EAS AF: 0.215

Gnomad SAS AF: 0.424

Gnomad FIN AF: 0.528

Gnomad MID AF: 0.253

Gnomad NFE AF: 0.489

Gnomad OTH AF: 0.390

GnomAD3 exomes AF: 0.426 AC: 107176 AN: 251470 Hom.: 24298 AF XY: 0.432 AC XY: 58726 AN XY: 135906

Gnomad AFR exome AF: 0.204

Gnomad AMR exome AF: 0.417

Gnomad ASJ exome AF: 0.329

Gnomad EAS exome AF: 0.198

Gnomad SAS exome AF: 0.427

Gnomad FIN exome AF: 0.528

Gnomad NFE exome AF: 0.487

Gnomad OTH exome AF: 0.428

GnomAD4 exome AF: 0.470 AC: 686512 AN: 1461782 Hom.: 164961 Cov.: 64 AF XY: 0.469 AC XY: 341410 AN XY: 727196

Gnomad4 AFR exome AF: 0.201

Gnomad4 AMR exome AF: 0.415

Gnomad4 ASJ exome AF: 0.326

Gnomad4 EAS exome AF: 0.246

Gnomad4 SAS exome AF: 0.432

Gnomad4 FIN exome AF: 0.524

Gnomad4 NFE exome AF: 0.494

Gnomad4 OTH exome AF: 0.433

GnomAD4 genome AF: 0.391 AC: 59468 AN: 151928 Hom.: 12850 Cov.: 30 AF XY: 0.391 AC XY: 29042 AN XY: 74208

Gnomad4 AFR AF: 0.212

Gnomad4 AMR AF: 0.417

Gnomad4 ASJ AF: 0.318

Gnomad4 EAS AF: 0.215

Gnomad4 SAS AF: 0.425

Gnomad4 FIN AF: 0.528

Gnomad4 NFE AF: 0.489

Gnomad4 OTH AF: 0.390

Alfa AF: 0.453 Hom.: 40090

Bravo AF: 0.370

TwinsUK AF: 0.497 AC: 1842

ALSPAC AF: 0.485 AC: 1868

ESP6500AA AF: 0.222 AC: 977

ESP6500EA AF: 0.480 AC: 4126

ExAC AF: 0.426 AC: 51700

Asia WGS AF: 0.303 AC: 1053 AN: 3478

EpiCase AF: 0.478

EpiControl AF: 0.469

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

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	- -
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.Ser707Asn in exon 12 of MYPN: This variant is not expected to have clinical si gnificance because it has been identified in 48% (4126/8600) of European America n chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.ed u/EVS/; dbSNP rs7916821). -
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	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -

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	Benign	0.15
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.54
Cadd	Benign	17
Dann	Uncertain	0.99
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.052
FATHMM_MKL	Benign	0.40	N
LIST_S2	Benign	0.78	T;T;.;T
MetaRNN	Benign	0.0014	T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.6	L;.;L;.
MutationTaster	Benign	0.97	P;P;P
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.25	N;N;N;.
REVEL	Benign	0.097
Sift	Benign	0.27	T;T;T;.
Sift4G	Benign	0.31	T;T;T;T
Polyphen		0.026	B;B;B;.
Vest4		0.046
MPC		0.13
ClinPred		0.0042	T
GERP RS		4.7
Varity_R		0.070
gMVP		0.11

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs7916821; hg19: chr10-69933969; COSMIC: COSV62741239;