10-68210307-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_032578.4(MYPN):​c.3815C>T​(p.Pro1272Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,428 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

MYPN
NM_032578.4 missense

Scores

3
6
10

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 3.82
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.28011495).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
MYPNNM_032578.4 linkuse as main transcriptc.3815C>T p.Pro1272Leu missense_variant 20/20 ENST00000358913.10
LOC124902443XR_007062176.1 linkuse as main transcriptn.127+4981G>A intron_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
MYPNENST00000358913.10 linkuse as main transcriptc.3815C>T p.Pro1272Leu missense_variant 20/201 NM_032578.4 P1Q86TC9-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461428
Hom.:
0
Cov.:
32
AF XY:
0.00000138
AC XY:
1
AN XY:
727024
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenMay 01, 2019- -
Dilated cardiomyopathy 1KK Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpApr 09, 2018This sequence change replaces proline with leucine at codon 1272 of the MYPN protein (p.Pro1272Leu). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and leucine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MYPN-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.27
BayesDel_addAF
Uncertain
0.11
D
BayesDel_noAF
Uncertain
-0.080
CADD
Uncertain
25
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.13
.;.;.;T
Eigen
Uncertain
0.67
Eigen_PC
Pathogenic
0.67
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Benign
0.82
T;T;.;T
M_CAP
Benign
0.050
D
MetaRNN
Benign
0.28
T;T;T;T
MetaSVM
Benign
-0.54
T
MutationAssessor
Benign
1.9
L;.;L;.
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Uncertain
0.60
T
PROVEAN
Uncertain
-2.7
D;D;D;.
REVEL
Benign
0.22
Sift
Uncertain
0.0030
D;D;D;.
Sift4G
Benign
0.065
T;T;T;T
Polyphen
1.0
D;D;D;.
Vest4
0.35
MutPred
0.43
Loss of disorder (P = 0.0206);.;Loss of disorder (P = 0.0206);.;
MVP
0.84
MPC
0.49
ClinPred
0.98
D
GERP RS
5.9
Varity_R
0.26
gMVP
0.51

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1554852276; hg19: chr10-69970064; API