rs147596628
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Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6BS1BS2
The NM_032578.4(MYPN):c.1130G>A(p.Arg377Gln) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000894 in 1,611,770 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00055 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00093 ( 3 hom. )
Consequence
MYPN
NM_032578.4 missense, splice_region
NM_032578.4 missense, splice_region
Scores
3
16
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 4.34
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 -9 ACMG points.
BP6
Variant 10-68145526-G-A is Benign according to our data. Variant chr10-68145526-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 191749.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, Uncertain_significance=4}. Variant chr10-68145526-G-A is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000546 (83/152106) while in subpopulation NFE AF= 0.000897 (61/67988). AF 95% confidence interval is 0.000716. There are 0 homozygotes in gnomad4. There are 31 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High AC in GnomAd4 at 83 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MYPN | NM_032578.4 | c.1130G>A | p.Arg377Gln | missense_variant, splice_region_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.1130G>A | p.Arg377Gln | missense_variant, splice_region_variant | 4/20 | 1 | NM_032578.4 | ENSP00000351790.5 |
Frequencies
GnomAD3 genomes AF: 0.000546 AC: 83AN: 151990Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000534 AC: 134AN: 251008Hom.: 0 AF XY: 0.000464 AC XY: 63AN XY: 135660
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GnomAD4 exome AF: 0.000930 AC: 1358AN: 1459664Hom.: 3 Cov.: 29 AF XY: 0.000916 AC XY: 665AN XY: 726302
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GnomAD4 genome AF: 0.000546 AC: 83AN: 152106Hom.: 0 Cov.: 32 AF XY: 0.000417 AC XY: 31AN XY: 74338
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:4Benign:6
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:2Benign:2
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Apr 30, 2021 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | May 12, 2021 | In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Reported in ClinVar (ClinVar Variant ID# 191749; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 23861362, 28050010) - |
Uncertain significance, criteria provided, single submitter | research | Biesecker Lab/Clinical Genomics Section, National Institutes of Health | Jun 24, 2013 | - - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Oct 01, 2023 | MYPN: BP4 - |
not specified Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 09, 2015 | The p.Arg377Gln variant in MYPN has not been previously reported in individuals with cardiomyopathy, but has been identified in 0.1% (13/11570) of Latino chromo somes and 43/66674 European chromosomes by the Exome Aggregation Consortium (ExA C, http://exac.broadinstitute.org; dbSNP rs147596628). Computational prediction tools and conservation analysis suggest that this variant may not impact the pro tein, though this information is not predictive enough to rule out pathogenicity . This variant is located in the last base of the exon, which is part of the 5' splice region. Computational tools do suggest an impact to splicing; however, th is information is not predictive enough to determine pathogenicity. In summary, in the presence of conflicting data, the clinical significance of the p.Arg377Gl n variant is uncertain. - |
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 05, 2024 | Variant summary: MYPN c.1130G>A (p.Arg377Gln) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00053 in 251008 control chromosomes (gnomAD). The observed variant frequency is approximately 11 fold of the estimated maximal expected allele frequency for a pathogenic variant in MYPN causing Cardiomyopathy phenotype (5e-05), strongly suggesting that the variant is benign. c.1130G>A has been reported in the literature in at-least one pediatric DCM proband without strong evidence for causality (example: Khan-2022). This report does not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 34935411). ClinVar contains an entry for this variant (Variation ID: 191749). Based on the evidence outlined above, the variant was classified as likely benign. - |
Dilated cardiomyopathy 1KK Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 15, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | Dec 11, 2015 | - - |
Cardiomyopathy Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego | Jan 10, 2019 | - - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 05, 2019 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
.;.;.;T;.
Eigen
Benign
Eigen_PC
Uncertain
FATHMM_MKL
Benign
D
LIST_S2
Uncertain
D;D;.;D;D
M_CAP
Benign
T
MetaRNN
Benign
T;T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
L;.;L;.;L
PrimateAI
Benign
T
PROVEAN
Benign
N;N;N;.;N
REVEL
Benign
Sift
Benign
T;T;T;.;T
Sift4G
Benign
T;T;T;T;T
Polyphen
B;B;B;.;D
Vest4
MVP
MPC
0.16
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: 0
Find out detailed SpliceAI scores and Pangolin per-transcript scores at