rs199476402

chr10-68122075-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_032578.4(MYPN):c.637A>G(p.Ile213Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I213N) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYPN NM_032578.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2 O:1
• Conservation: PhyloP100: 1.96

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16355741).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYPN	NM_032578.4	c.637A>G	p.Ile213Val	missense_variant	2/20	ENST00000358913.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYPN	ENST00000358913.10	c.637A>G	p.Ile213Val	missense_variant	2/20	1	NM_032578.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 16, 2015

The p.Ile213Val variant in MYPN has been reported in a Caucasian adult with infa ntile-onset DCM, but was not detected in her affected sister (Purevjav 2012). Th is variant was absent from large population studies. Computational prediction to ols and conservation analysis suggest that the p.Ile213Val variant may not impac t the protein, though this information is not predictive enough to rule out path ogenicity. In summary, the clinical significance of the p.Ile213Val variant is u ncertain. -

Dilated cardiomyopathy 1KK Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

ClinVar Staff, National Center for Biotechnology Information (NCBI)

Jun 27, 2013

- -

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	0.13
BayesDel_addAF	Uncertain	0.069	D
BayesDel_noAF	Benign	-0.14
Cadd	Benign	16
Dann	Benign	0.94
Eigen	Benign	-0.086
Eigen_PC	Benign	0.10
FATHMM_MKL	Benign	0.58	D
LIST_S2	Benign	0.66	T;.;T
M_CAP	Benign	0.0095	T
MetaRNN	Benign	0.16	T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.8	L;L;L
MutationTaster	Benign	1.0	D;N;N;N
PrimateAI	Benign	0.47	T
PROVEAN	Benign	0.010	N;N;N
REVEL	Benign	0.21
Sift	Benign	0.42	T;T;T
Sift4G	Benign	0.62	T;T;T
Polyphen		0.070	B;B;B
Vest4		0.39
MutPred		0.14		Loss of catalytic residue at A217 (P = 0.2226);Loss of catalytic residue at A217 (P = 0.2226);Loss of catalytic residue at A217 (P = 0.2226);
MVP		0.72
MPC		0.11
ClinPred		0.32	T
GERP RS		5.7
Varity_R		0.089
gMVP		0.17

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: rs199476402; hg19: chr10-69881832;