rs10997948

Variant names:

• chr10-68150045-G-A
• rs10997948
• NM_032578.4:c.1251G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_032578.4(MYPN):​c.1251G>A​(p.Gln417Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0834 in 1,611,476 control chromosomes in the GnomAD database, including 6,240 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.099 (898 hom., cov: 32)
  • Exomes 𝑓: 0.082 (5342 hom.)
• Consequence: MYPN NM_032578.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5 O:1
• Conservation: PhyloP100: 2.52
• Publications: 9 publications found

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]

MYPN Gene-Disease associations (from GenCC):

• MYPN-related myopathy

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen
• cap myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• childhood-onset nemaline myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial isolated restrictive cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• dilated cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• dilated cardiomyopathy 1KK

  Inheritance: AD Classification: LIMITED Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae)
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

LOC107984240 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 10-68150045-G-A is Benign according to our data. Variant chr10-68150045-G-A is described in ClinVar as Benign. ClinVar VariationId is 31794.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.52 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.153 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYPN	NM_032578.4	c.1251G>A	p.Gln417Gln	synonymous_variant	Exon 6 of 20	ENST00000358913.10	NP_115967.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYPN	ENST00000358913.10	c.1251G>A	p.Gln417Gln	synonymous_variant	Exon 6 of 20	1	NM_032578.4	ENSP00000351790.5

Frequencies

GnomAD3 genomes AF: 0.0992 AC: 15076 AN: 151998 Hom.: 894 Cov.: 32

Gnomad AFR AF: 0.156

Gnomad AMI AF: 0.138

Gnomad AMR AF: 0.0740

Gnomad ASJ AF: 0.123

Gnomad EAS AF: 0.00519

Gnomad SAS AF: 0.0921

Gnomad FIN AF: 0.0581

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.0825

Gnomad OTH AF: 0.0937

GnomAD2 exomes AF: 0.0811 AC: 20383 AN: 251326 AF XY: 0.0831

Gnomad AFR exome AF: 0.157

Gnomad AMR exome AF: 0.0479

Gnomad ASJ exome AF: 0.127

Gnomad EAS exome AF: 0.00745

Gnomad FIN exome AF: 0.0580

Gnomad NFE exome AF: 0.0858

Gnomad OTH exome AF: 0.0853

GnomAD4 exome AF: 0.0818 AC: 119348 AN: 1459360 Hom.: 5342 Cov.: 31 AF XY: 0.0830 AC XY: 60267 AN XY: 726138

African (AFR) AF: 0.154 AC: 5155 AN: 33404

American (AMR) AF: 0.0498 AC: 2228 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.126 AC: 3300 AN: 26110

East Asian (EAS) AF: 0.00345 AC: 137 AN: 39676

South Asian (SAS) AF: 0.104 AC: 8933 AN: 86206

European-Finnish (FIN) AF: 0.0591 AC: 3153 AN: 53388

Middle Eastern (MID) AF: 0.123 AC: 706 AN: 5760

European-Non Finnish (NFE) AF: 0.0815 AC: 90464 AN: 1109784

Other (OTH) AF: 0.0874 AC: 5272 AN: 60314

GnomAD4 genome AF: 0.0992 AC: 15090 AN: 152116 Hom.: 898 Cov.: 32 AF XY: 0.0976 AC XY: 7260 AN XY: 74372

African (AFR) AF: 0.156 AC: 6477 AN: 41452

American (AMR) AF: 0.0738 AC: 1128 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.123 AC: 427 AN: 3470

East Asian (EAS) AF: 0.00501 AC: 26 AN: 5188

South Asian (SAS) AF: 0.0916 AC: 442 AN: 4826

European-Finnish (FIN) AF: 0.0581 AC: 614 AN: 10566

Middle Eastern (MID) AF: 0.126 AC: 37 AN: 294

European-Non Finnish (NFE) AF: 0.0826 AC: 5616 AN: 68016

Other (OTH) AF: 0.0932 AC: 197 AN: 2114

Alfa AF: 0.0906 Hom.: 1497

Bravo AF: 0.103

Asia WGS AF: 0.0610 AC: 212 AN: 3478

EpiCase AF: 0.0878

EpiControl AF: 0.0865

ClinVar

Significance: Benign

Submissions summary: Benign:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Nov 13, 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. -

Oct 29, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Gln417Gln in exon 7 of MYPN: This variant is not expected to have clinical sig nificance because it has been identified in 16% (702/4406) of African American c hromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/E VS/; dbSNPrs10997948). -

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 12, 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	-0.46
CADD	Benign	9.1
DANN	Benign	0.61
PhyloP100		2.5
Mutation Taster		=93/7	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs10997948; hg19: chr10-69909802;