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NM_001164508.2(NEB):c.23742+2T>C AND Nemaline myopathy 2

Germline classification:
Likely pathogenic (3 submissions)
Last evaluated:
Jan 31, 2024
Review status:
2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts
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:
RCV000416472.10

Allele description [Variation Report for NM_001164508.2(NEB):c.23742+2T>C]

NM_001164508.2(NEB):c.23742+2T>C

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.23742+2T>C
HGVS:
  • NC_000002.12:g.151505476A>G
  • NG_009382.2:g.234012T>C
  • NG_017162.2:g.100576A>G
  • NM_001164507.2:c.23742+2T>C
  • NM_001164508.2:c.23742+2T>CMANE SELECT
  • NM_001271208.2:c.23847+2T>C
  • NM_004543.5:c.18639+2T>C
  • LRG_202t1:c.23847+2T>C
  • LRG_202:g.234012T>C
  • NC_000002.11:g.152361990A>G
  • NM_001271208.1:c.23847+2T>C
Links:
dbSNP: rs545937015
NCBI 1000 Genomes Browser:
rs545937015
Molecular consequence:
  • NM_001164507.2:c.23742+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001164508.2:c.23742+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001271208.2:c.23847+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_004543.5:c.18639+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]

Condition(s)

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

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000494237Knight Diagnostic Laboratories, Oregon Health and Sciences University - CSER-NextGen
criteria provided, single submitter

(ACMG Guidelines, 2015)
Likely pathogenic
(Jun 27, 2016)
germlineclinical testing

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

SCV000640726Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Likely pathogenic
(Jan 31, 2024)
germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV001459172Natera, Inc.
no assertion criteria provided
Likely pathogenic
(Sep 16, 2020)
germlineclinical testing

Summary from all submissions

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

Citations

PubMed

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]
PMID:
25741868
PMCID:
PMC4544753

Splicing in action: assessing disease causing sequence changes.

Baralle D, Baralle M.

J Med Genet. 2005 Oct;42(10):737-48. Review.

PubMed [citation]
PMID:
16199547
PMCID:
PMC1735933
See all PubMed Citations (4)

Details of each submission

From Knight Diagnostic Laboratories, Oregon Health and Sciences University - CSER-NextGen, SCV000494237.1

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

Description

The c.23847+2T>C splice variant in the NEB gene has not been previously reported in patients and this variant is absent (1000 Genomes; Exome Sequencing Project) or reported at low frequency in the population databases (ExAC = 0.01%; only 2 alleles). Splice-site, nonsense, and frameshift variants have been described in the NEB gene in multiple affected individuals (including nonsense and frameshift variants downstream of this variant) and thus, loss of function is a known mechanism of disease (GeneReviews: North and Ryan, 2015). Multiple in silico algorithms show high evolutionary conservation (CADD = 18.14; GERP=5.48), and in silico splicing algorithms predict this variant will cause altered splicing (Human Splice Finder=Broken WT Donor Site; SPIDEX=-3.228). Therefore, this collective evidence supports the classification of the c.23847+2T>C variant as a Likely pathogenic variant for Nemaline Myopathy 2. We have confirmed this finding in our laboratory using Sanger sequencing.

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000640726.7

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

This sequence change affects a donor splice site in intron 166 of the NEB gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in NEB are known to be pathogenic (PMID: 25205138). This variant is present in population databases (rs545937015, gnomAD 0.008%). This variant has not been reported in the literature in individuals affected with NEB-related conditions. ClinVar contains an entry for this variant (Variation ID: 375408). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.

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

From Natera, Inc., SCV001459172.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Feb 1, 2025