2-151643290-C-T
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Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2PP5_ModerateBP4
The NM_001164507.2(NEB):c.8020G>A(p.Glu2674Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000217 in 1,613,838 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000023 ( 1 hom. )
Consequence
NEB
NM_001164507.2 missense
NM_001164507.2 missense
Scores
2
6
10
Clinical Significance
Conservation
PhyloP100: 7.75
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 3 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 2-151643290-C-T is Pathogenic according to our data. Variant chr2-151643290-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 570495.Status of the report is criteria_provided_single_submitter, 1 stars.
BP4
Computational evidence support a benign effect (MetaRNN=0.33210903). . Strength limited to SUPPORTING due to the PP5.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NEB | NM_001164507.2 | c.8020G>A | p.Glu2674Lys | missense_variant | 58/182 | ENST00000427231.7 | |
NEB | NM_001164508.2 | c.8020G>A | p.Glu2674Lys | missense_variant | 58/182 | ENST00000397345.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NEB | ENST00000397345.8 | c.8020G>A | p.Glu2674Lys | missense_variant | 58/182 | 5 | NM_001164508.2 | P5 | |
NEB | ENST00000427231.7 | c.8020G>A | p.Glu2674Lys | missense_variant | 58/182 | 5 | NM_001164507.2 | A2 | |
NEB | ENST00000409198.5 | c.8020G>A | p.Glu2674Lys | missense_variant | 58/150 | 5 |
Frequencies
GnomAD3 genomes AF: 0.0000132 AC: 2AN: 152082Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000120 AC: 3AN: 249032Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135100
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GnomAD4 exome AF: 0.0000226 AC: 33AN: 1461638Hom.: 1 Cov.: 31 AF XY: 0.0000261 AC XY: 19AN XY: 727104
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GnomAD4 genome AF: 0.0000131 AC: 2AN: 152200Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74414
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ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Nemaline myopathy 2 Pathogenic:1Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Nov 11, 2019 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 15, 2023 | This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 2674 of the NEB protein (p.Glu2674Lys). This variant is present in population databases (rs369224273, gnomAD 0.003%). This missense change has been observed in individual(s) with clinical features of autosomal recessive nemaline myopathy 2 (Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 570495). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Pathogenic
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D;D;.;.
M_CAP
Benign
D
MetaRNN
Benign
T;T;T;T;T;T;T
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
Benign
T;D;.;D;T;.;.
Sift4G
Uncertain
D;D;D;D;D;D;D
Polyphen
0.98
.;.;.;.;D;.;.
Vest4
MVP
MPC
0.14
ClinPred
D
GERP RS
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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