rs201707021
Positions:
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 2P and 7B. PM2BP4_ModerateBP6BS1
The NM_001164507.2(NEB):c.8719G>A(p.Gly2907Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000253 in 1,613,902 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00097 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00018 ( 0 hom. )
Consequence
NEB
NM_001164507.2 missense
NM_001164507.2 missense
Scores
6
7
5
Clinical Significance
Conservation
PhyloP100: 7.57
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 Likely_benign. Variant got -5 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (MetaRNN=0.0702765).
BP6
?
Variant 2-151640027-C-T is Benign according to our data. Variant chr2-151640027-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 198321.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=2}.
BS1
?
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000972 (148/152290) while in subpopulation AFR AF= 0.0033 (137/41572). AF 95% confidence interval is 0.00285. There are 0 homozygotes in gnomad4. There are 73 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NEB | NM_001164507.2 | c.8719G>A | p.Gly2907Ser | missense_variant | 62/182 | ENST00000427231.7 | |
NEB | NM_001164508.2 | c.8719G>A | p.Gly2907Ser | missense_variant | 62/182 | ENST00000397345.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NEB | ENST00000397345.8 | c.8719G>A | p.Gly2907Ser | missense_variant | 62/182 | 5 | NM_001164508.2 | P5 | |
NEB | ENST00000427231.7 | c.8719G>A | p.Gly2907Ser | missense_variant | 62/182 | 5 | NM_001164507.2 | A2 | |
NEB | ENST00000409198.5 | c.8719G>A | p.Gly2907Ser | missense_variant | 62/150 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.000973 AC: 148AN: 152172Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000301 AC: 75AN: 249012Hom.: 0 AF XY: 0.000281 AC XY: 38AN XY: 135072
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GnomAD4 exome AF: 0.000178 AC: 260AN: 1461612Hom.: 0 Cov.: 32 AF XY: 0.000180 AC XY: 131AN XY: 727104
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GnomAD4 genome ? AF: 0.000972 AC: 148AN: 152290Hom.: 0 Cov.: 32 AF XY: 0.000980 AC XY: 73AN XY: 74476
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:3
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 21, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Sep 12, 2014 | - - |
Nemaline myopathy 2 Uncertain:1Benign:1
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Jan 24, 2020 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 24, 2024 | - - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 08, 2024 | The c.8719G>A (p.G2907S) alteration is located in exon 62 (coding exon 60) of the NEB gene. This alteration results from a G to A substitution at nucleotide position 8719, causing the glycine (G) at amino acid position 2907 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
NEB-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | May 23, 2023 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
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
Uncertain
D
MutationAssessor
Pathogenic
H;H;.;H;H;H;H
MutationTaster
Benign
D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
N;D;.;D;N;.;.
REVEL
Uncertain
Sift
Benign
T;D;.;D;T;.;.
Sift4G
Pathogenic
D;D;D;D;D;D;D
Polyphen
1.0
.;.;.;.;D;.;.
Vest4
MVP
MPC
0.34
ClinPred
T
GERP RS
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gMVP
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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