10-68166434-G-C

Variant names:

• chr10-68166434-G-C
• rs1464184643
• NM_032578.4:c.1741G>C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_032578.4(MYPN):​c.1741G>C​(p.Val581Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYPN NM_032578.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.94

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31119615).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYPN	NM_032578.4	c.1741G>C	p.Val581Leu	missense_variant	Exon 10 of 20	ENST00000358913.10	NP_115967.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYPN	ENST00000358913.10	c.1741G>C	p.Val581Leu	missense_variant	Exon 10 of 20	1	NM_032578.4	ENSP00000351790.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 78

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Jan 20, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Val581Leu variant in MYPN has not been previously reported in individuals with cardiomyopathy or in large population studies. Computational prediction too ls and conservation analysis suggest that the p.Val581Leu variant may impact the protein, though this information is not predictive enough to determine pathogen icity. In summary, the clinical significance of the p.Val581Leu variant is uncer tain. -

Cardiovascular phenotype Uncertain:1

Feb 16, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.V581L variant (also known as c.1741G>C), located in coding exon 9 of the MYPN gene, results from a G to C substitution at nucleotide position 1741. The valine at codon 581 is replaced by leucine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.036	T
BayesDel_noAF	Benign	-0.29
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.025	.;.;.;T
Eigen	Uncertain	0.67
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.85	T;D;.;D
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.31	T;T;T;T
MetaSVM	Benign	-0.53	T
MutationAssessor	Uncertain	2.4	M;.;M;.
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-0.50	N;N;N;.
REVEL	Benign	0.12
Sift	Benign	0.25	T;T;T;.
Sift4G	Benign	0.69	T;T;T;T
Polyphen		0.99	D;D;D;.
Vest4		0.41
MutPred		0.15		Loss of methylation at K577 (P = 0.0786);.;Loss of methylation at K577 (P = 0.0786);.;
MVP		0.72
MPC		0.52
ClinPred		0.98	D
GERP RS		5.3
Varity_R		0.24
gMVP		0.45

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: rs1464184643; hg19: chr10-69926191;