NM_001164508.2(NEB):c.13147C>T (p.Gln4383Ter) AND Nemaline myopathy 2

Clinical significance:Pathogenic/Likely pathogenic (Last evaluated: Apr 15, 2020)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
2 submissions [Details]
Record status:

Allele description [Variation Report for NM_001164508.2(NEB):c.13147C>T (p.Gln4383Ter)]

NM_001164508.2(NEB):c.13147C>T (p.Gln4383Ter)

NEB:nebulin [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
Genomic location:
Preferred name:
NM_001164508.2(NEB):c.13147C>T (p.Gln4383Ter)
  • NC_000002.12:g.151603685G>A
  • NG_009382.2:g.135803C>T
  • NM_001164507.2:c.13147C>T
  • NM_001164508.2:c.13147C>TMANE SELECT
  • NM_001271208.2:c.13147C>T
  • NM_004543.5:c.11601+6124C>T
  • NP_001157979.2:p.Gln4383Ter
  • NP_001157980.2:p.Gln4383Ter
  • NP_001258137.2:p.Gln4383Ter
  • LRG_202t1:c.13147C>T
  • LRG_202:g.135803C>T
  • NC_000002.11:g.152460199G>A
  • NM_001271208.1:c.13147C>T
  • p.Gln4383Ter
Protein change:
dbSNP: rs1212374733
NCBI 1000 Genomes Browser:
Molecular consequence:
  • NM_004543.5:c.11601+6124C>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001164507.2:c.13147C>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001164508.2:c.13147C>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001271208.2:c.13147C>T - nonsense - [Sequence Ontology: SO:0001587]


Nemaline myopathy 2 (NEM2)
Nemaline myopathy caused by mutation in the nebulin gene; Nemaline myopathy 2, autosomal recessive
MONDO: MONDO:0009725; MedGen: C1850569; OMIM: 256030

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
SCV001164465Broad Institute Rare Disease Group, Broad Institutecriteria provided, single submitter
Likely pathogenic
(Dec 3, 2018)

PubMed (1)
[See all records that cite this PMID]

SCV001225725Invitaecriteria provided, single submitter
(Apr 15, 2020)
germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedresearch
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing



Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

Mutation update: the spectra of nebulin variants and associated myopathies.

Lehtokari VL, Kiiski K, Sandaradura SA, Laporte J, Repo P, Frey JA, Donner K, Marttila M, Saunders C, Barth PG, den Dunnen JT, Beggs AH, Clarke NF, North KN, Laing NG, Romero NB, Winder TL, Pelin K, Wallgren-Pettersson C.

Hum Mutat. 2014 Dec;35(12):1418-26. doi: 10.1002/humu.22693.

PubMed [citation]
See all PubMed Citations (3)

Details of each submission

From Broad Institute Rare Disease Group, Broad Institute, SCV001164465.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedresearch PubMed (1)


The heterozygous p.Gln4383Ter variant in NEB was identified by our study in the compound heterozygous state, with a VUS, in one individual with nemaline myopathy. This variant was absent from large population studies. This nonsense variant leads to a premature termination codon at position 4383, which is predicted to lead to a truncated or absent protein. Loss of function of the NEB gene is an established disease mechanism for autosomal recessive nemaline myopathy. In summary, although additional studies are required to fully establish clinical significance, the p.Gln4383Ter variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PVS1 (Richards 2015).

OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV001225725.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)


This variant occurs in a region of NEB (Exons 82-105) consisting of three highly homologous 8-exon repeat units (exons 82-89, exons 90-97, exons 98-105). Sequence variants in this region can be detected, but this assay cannot determine which of the three repeat units is affected, and zygosity is often ambiguous. All variants in this region are reported relative to the exon 82-89 repeat. This sequence change creates a premature translational stop signal (p.Gln4383*) in the NEB gene. It is expected to result in an absent or disrupted protein product. This variant has not been reported in the literature in individuals with NEB-related conditions. Loss-of-function variants in NEB are known to be pathogenic (PMID: 25205138). For these reasons, this variant has been classified as Pathogenic.

OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Oct 30, 2021

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