rs535795936
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Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBS1_SupportingBS2
The ENST00000358913.10(MYPN):āc.1096T>Cā(p.Ser366Pro) variant causes a missense change. The variant allele was found at a frequency of 0.0000192 in 1,613,568 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Genomes: š 0.000033 ( 0 hom., cov: 32)
Exomes š: 0.000018 ( 2 hom. )
Consequence
MYPN
ENST00000358913.10 missense
ENST00000358913.10 missense
Scores
1
10
8
Clinical Significance
Conservation
PhyloP100: 5.25
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]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -7 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.10422903).
BS1
Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0000328 (5/152314) while in subpopulation SAS AF= 0.00104 (5/4824). AF 95% confidence interval is 0.000408. There are 0 homozygotes in gnomad4. There are 3 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
High AC in GnomAd4 at 5 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MYPN | NM_032578.4 | c.1096T>C | p.Ser366Pro | missense_variant | 4/20 | ENST00000358913.10 | NP_115967.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MYPN | ENST00000358913.10 | c.1096T>C | p.Ser366Pro | missense_variant | 4/20 | 1 | NM_032578.4 | ENSP00000351790 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000329 AC: 5AN: 152196Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251114Hom.: 1 AF XY: 0.0000368 AC XY: 5AN XY: 135726
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GnomAD4 exome AF: 0.0000178 AC: 26AN: 1461254Hom.: 2 Cov.: 30 AF XY: 0.0000261 AC XY: 19AN XY: 726982
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GnomAD4 genome AF: 0.0000328 AC: 5AN: 152314Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3AN XY: 74476
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Oct 02, 2020 | - - |
Dilated cardiomyopathy 1KK Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jul 08, 2022 | This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 366 of the MYPN protein (p.Ser366Pro). This variant is present in population databases (rs535795936, gnomAD 0.01%). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 31983221). ClinVar contains an entry for this variant (Variation ID: 579816). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or 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. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 09, 2022 | The p.S366P variant (also known as c.1096T>C), located in coding exon 3 of the MYPN gene, results from a T to C substitution at nucleotide position 1096. The serine at codon 366 is replaced by proline, an amino acid with similar properties. This alteration has been reported in a dilated cardiomyopathy (DCM) cohort; however, clinical details were limited (Mazzarotto F et al. Circulation, 2020 02;141:387-398). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
.;.;.;T;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;.;D;D
M_CAP
Benign
D
MetaRNN
Benign
T;T;T;T;T
MetaSVM
Uncertain
T
MutationAssessor
Uncertain
M;.;M;.;M
MutationTaster
Benign
D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
N;D;D;.;D
REVEL
Benign
Sift
Uncertain
D;D;D;.;D
Sift4G
Uncertain
D;D;D;D;D
Polyphen
D;P;D;.;D
Vest4
MutPred
Loss of phosphorylation at S366 (P = 0.0149);.;Loss of phosphorylation at S366 (P = 0.0149);.;Loss of phosphorylation at S366 (P = 0.0149);
MVP
MPC
0.45
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at