Genetic Variant NM_032578.4:c.1345G>A (chr10-68158513-G-A) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_032578.4(MYPN):c.1345G>A(p.Gly449Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. G449C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

MYPN
NM_032578.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.64

Publications

0 publications found

Variant links:

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 links:

RN7SKP202 (HGNC:45926): (RN7SK pseudogene 202)

RN7SKP202 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.969

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032578.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MYPN	NM_032578.4	MANE Select	c.1345G>A	p.Gly449Ser	missense	Exon 7 of 20	NP_115967.2	Q86TC9-1
MYPN	NM_001256267.2		c.1345G>A	p.Gly449Ser	missense	Exon 8 of 21	NP_001243196.1	Q86TC9-1
MYPN	NM_001256268.2		c.463G>A	p.Gly155Ser	missense	Exon 11 of 24	NP_001243197.1	A0A087WX60

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MYPN	ENST00000358913.10	TSL:1 MANE Select	c.1345G>A	p.Gly449Ser	missense	Exon 7 of 20	ENSP00000351790.5	Q86TC9-1
MYPN	ENST00000540630.6	TSL:1	c.1399G>A	p.Gly467Ser	missense	Exon 7 of 20	ENSP00000441668.3	A0A8J9ASZ5
MYPN	ENST00000613327.5	TSL:1	c.1345G>A	p.Gly449Ser	missense	Exon 8 of 21	ENSP00000480757.2	Q86TC9-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Dilated cardiomyopathy 1KK (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.67

BayesDel_addAF

Pathogenic

0.39

BayesDel_noAF

Pathogenic

0.32

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.14

Eigen

Pathogenic

0.87

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.95

M_CAP

Uncertain

0.14

MetaRNN

Pathogenic

0.97

MetaSVM

Uncertain

0.53

MutationAssessor

Uncertain

2.7

PhyloP100

7.6

PrimateAI

Pathogenic

0.83

PROVEAN

Uncertain

-3.9

REVEL

Pathogenic

0.82

Sift

Uncertain

0.023

Sift4G

Benign

0.14

Polyphen

1.0

Vest4

0.79

MutPred

0.92

Gain of disorder (P = 0.07)

MVP

0.88

MPC

0.61

ClinPred

0.99

GERP RS

5.6

Varity_R

0.64

gMVP

0.71

Mutation Taster

=48/52

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over