Menu
GeneBe

rs769345284

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_001164507.2(NEB):c.21076C>T(p.Arg7026Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000171 in 1,459,460 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

NEB
NM_001164507.2 stop_gained

Scores

3
3
1

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 5.90
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 2-151537898-G-A is Pathogenic according to our data. Variant chr2-151537898-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 190457.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-151537898-G-A is described in Lovd as [Pathogenic]. Variant chr2-151537898-G-A is described in Lovd as [Likely_pathogenic]. Variant chr2-151537898-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
NEBNM_001164507.2 linkuse as main transcriptc.21076C>T p.Arg7026Ter stop_gained 140/182 ENST00000427231.7
NEBNM_001164508.2 linkuse as main transcriptc.21076C>T p.Arg7026Ter stop_gained 140/182 ENST00000397345.8
LOC124906081XR_007087266.1 linkuse as main transcriptn.123G>A non_coding_transcript_exon_variant 2/3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
NEBENST00000397345.8 linkuse as main transcriptc.21076C>T p.Arg7026Ter stop_gained 140/1825 NM_001164508.2 P5P20929-2
NEBENST00000427231.7 linkuse as main transcriptc.21076C>T p.Arg7026Ter stop_gained 140/1825 NM_001164507.2 A2P20929-3

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.0000323
AC:
8
AN:
247458
Hom.:
0
AF XY:
0.0000447
AC XY:
6
AN XY:
134190
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000293
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000331
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000534
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000171
AC:
25
AN:
1459460
Hom.:
0
Cov.:
30
AF XY:
0.0000193
AC XY:
14
AN XY:
725866
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000225
Gnomad4 ASJ exome
AF:
0.0000384
Gnomad4 EAS exome
AF:
0.0000505
Gnomad4 SAS exome
AF:
0.0000117
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000162
Gnomad4 OTH exome
AF:
0.0000332
GnomAD4 genome
Cov.:
33
Alfa
AF:
0.0000508
Hom.:
0
ExAC
AF:
0.0000165
AC:
2
EpiCase
AF:
0.00
EpiControl
AF:
0.0000595

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Nemaline myopathy 2 Pathogenic:4
Pathogenic, criteria provided, single submitterresearchCenter for Genomic Medicine, King Faisal Specialist Hospital and Research CenterMar 14, 2024- -
Pathogenic, no assertion criteria providedclinical testingNatera, Inc.Sep 16, 2020- -
Pathogenic, criteria provided, single submitterclinical testingCounsylJan 06, 2017- -
Pathogenic, criteria provided, single submitterclinical testingInvitaeDec 22, 2023This sequence change creates a premature translational stop signal (p.Arg7026*) in the NEB gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NEB are known to be pathogenic (PMID: 25205138). This variant is present in population databases (rs769345284, gnomAD 0.005%). This premature translational stop signal has been observed in individuals with nemaline myopathy (PMID: 25205138, 26841830). ClinVar contains an entry for this variant (Variation ID: 190457). For these reasons, this variant has been classified as Pathogenic. -
Nemaline myopathy Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpMay 14, 2018Variant summary: NEB c.21076C>T (p.Arg7026X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (eg. c.24407_24410dupTGTT, p.Leu8137fsX18; c.24559C>T, p.Arg8187X). The variant allele was found at a frequency of 3.3e-05 in 244554 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in NEB causing Nemaline Myopathy 2 (3.3e-05 vs 0.0035), allowing no conclusion about variant significance. The variant, c.21076C>T, has been reported in the literature in individuals affected with Nemaline Myopathy 2 (Lehtokari_2014, Oliveira_2016, Park_2018), as well as in a family with recurrent fetal loss in the homozygous state (Shamseldin_2015). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. -
Arthrogryposis multiplex congenita 6 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsSep 03, 2023- -
Non-immune hydrops fetalis Pathogenic:1
Likely pathogenic, criteria provided, single submitterresearchDepartment Of Translational Genomics (developmental Genetics Section), King Faisal Specialist Hospital & Research CentreDec 15, 2013- -
Nemaline myopathy 2;C5543431:Arthrogryposis multiplex congenita 6 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsMar 23, 2022- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.52
D
BayesDel_noAF
Pathogenic
0.63
Cadd
Pathogenic
49
Dann
Uncertain
0.99
Eigen
Pathogenic
0.77
Eigen_PC
Uncertain
0.64
FATHMM_MKL
Uncertain
0.93
D
MutationTaster
Benign
1.0
A;A;A;A
Vest4
0.99
GERP RS
4.7

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs769345284; hg19: chr2-152394412; COSMIC: COSV50829439; API