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NM_001164508.2(NEB):c.21417+3A>G AND NEB-related disorder

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Jun 7, 2024
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV004737563.1

Allele description [Variation Report for NM_001164508.2(NEB):c.21417+3A>G]

NM_001164508.2(NEB):c.21417+3A>G

Genes:
NEB:nebulin [Gene - OMIM - HGNC]
RIF1:replication timing regulatory factor 1 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
2q23.3
Genomic location:
Preferred name:
NM_001164508.2(NEB):c.21417+3A>G
HGVS:
  • NC_000002.12:g.151533439T>C
  • NG_009382.2:g.206049A>G
  • NM_001164507.2:c.21417+776A>G
  • NM_001164508.2:c.21417+3A>GMANE SELECT
  • NM_001271208.2:c.21522+3A>G
  • NM_004543.5:c.16314+776A>G
  • LRG_202t1:c.21522+3A>G
  • LRG_202:g.206049A>G
  • NC_000002.11:g.152389953T>C
  • NM_001164508.2:c.21417+3A>G
  • NM_001271208.1:c.21522+3A>G
Links:
dbSNP: rs148950085
NCBI 1000 Genomes Browser:
rs148950085
Molecular consequence:
  • NM_001164507.2:c.21417+776A>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001164508.2:c.21417+3A>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001271208.2:c.21522+3A>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_004543.5:c.16314+776A>G - intron variant - [Sequence Ontology: SO:0001627]

Condition(s)

Name:
NEB-related disorder
Synonyms:
NEB-related condition; NEB-Related Disorders
Identifiers:

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV005360116PreventionGenetics, part of Exact Sciences
no assertion criteria provided
Pathogenic
(Jun 7, 2024) 		germlineclinical testing

Help

Summary from all submissions

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

Details of each submission

From PreventionGenetics, part of Exact Sciences, SCV005360116.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

The NEB c.21522+3A>G variant is predicted to interfere with splicing. This variant has been reported with a second NEB variant in many individuals with nemaline myopathy and has been described as a possible founder variant in East Asian populations (Wen et al. 2019. PubMed ID: 31696431; Yin et al. 2021. PubMed ID: 33742414; reported as c.21417+3A>G (NM_001164508) in Wang et al. 2020. PubMed ID: 32222963). This variant is reported in 0.22% of alleles in individuals of East Asian descent in gnomAD. RT-PCR studies suggest this variant impacts mRNA splicing, resulting in skipping of exon 144 of NM_001271208 (Wang et al. 2020. PubMed ID: 32222963). An additional study using RNA-seq analysis on muscle tissue confirms the c.21522+3A>G variant results in impaired splicing (Silverstein et al. 2024. PubMed ID: 38585796, peer review in progress). Another nucleotide change at the same position (c.21522+3A>C) has also been reported in an individual with nemaline myopathy and indicated to interfere with normal splicing (Cummings et al. 2017. PubMed ID: 28424332). This variant is interpreted as pathogenic.

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

Last Updated: Oct 25, 2025