rs369215974
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP6
The NM_001164507.2(NEB):c.6175G>A(p.Ala2059Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000109 in 1,603,152 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00011 ( 1 hom. )
Consequence
NEB
NM_001164507.2 missense
NM_001164507.2 missense
Scores
1
9
8
Clinical Significance
Conservation
PhyloP100: 4.86
Genes affected
NEB (HGNC:7720): (nebulin) This gene encodes nebulin, a giant protein component of the cytoskeletal matrix that coexists with the thick and thin filaments within the sarcomeres of skeletal muscle. In most vertebrates, nebulin accounts for 3 to 4% of the total myofibrillar protein. The encoded protein contains approximately 30-amino acid long modules that can be classified into 7 types and other repeated modules. Protein isoform sizes vary from 600 to 800 kD due to alternative splicing that is tissue-, species-,and developmental stage-specific. Of the 183 exons in the nebulin gene, at least 43 are alternatively spliced, although exons 143 and 144 are not found in the same transcript. Of the several thousand transcript variants predicted for nebulin, the RefSeq Project has decided to create three representative RefSeq records. Mutations in this gene are associated with recessive nemaline myopathy. [provided by RefSeq, Sep 2009]
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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;
BP6
?
Variant 2-151657991-C-T is Benign according to our data. Variant chr2-151657991-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 534007.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NEB | NM_001164507.2 | c.6175G>A | p.Ala2059Thr | missense_variant | 48/182 | ENST00000427231.7 | |
NEB | NM_001164508.2 | c.6175G>A | p.Ala2059Thr | missense_variant | 48/182 | ENST00000397345.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NEB | ENST00000397345.8 | c.6175G>A | p.Ala2059Thr | missense_variant | 48/182 | 5 | NM_001164508.2 | P5 | |
NEB | ENST00000427231.7 | c.6175G>A | p.Ala2059Thr | missense_variant | 48/182 | 5 | NM_001164507.2 | A2 | |
NEB | ENST00000409198.5 | c.6175G>A | p.Ala2059Thr | missense_variant | 48/150 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.000125 AC: 19AN: 152184Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000903 AC: 22AN: 243512Hom.: 1 AF XY: 0.0000834 AC XY: 11AN XY: 131908
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GnomAD4 exome AF: 0.000108 AC: 156AN: 1450850Hom.: 1 Cov.: 30 AF XY: 0.0000914 AC XY: 66AN XY: 721808
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GnomAD4 genome ? AF: 0.000125 AC: 19AN: 152302Hom.: 0 Cov.: 32 AF XY: 0.000107 AC XY: 8AN XY: 74462
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:3
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jan 22, 2022 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Dec 30, 2020 | - - |
See cases Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Dec 16, 2019 | ACMG classification criteria: PM2, BP1, BP4 - |
Nemaline myopathy 2 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 25, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Pathogenic
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;D;D;.;.
M_CAP
Benign
D
MetaRNN
Uncertain
D;D;D;D;D;D;D
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;M;.;M;M;M;M
MutationTaster
Benign
D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;.;N;N;.;.
REVEL
Benign
Sift
Uncertain
D;D;.;D;D;.;.
Sift4G
Uncertain
D;D;D;D;D;D;D
Polyphen
0.98
.;.;.;.;D;.;.
Vest4
MVP
MPC
0.33
ClinPred
T
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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