NM_001164508.2(NEB):c.24297_24300+1del AND Nemaline myopathy 2

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Sep 20, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV003515801.1

Allele description [Variation Report for NM_001164508.2(NEB):c.24297_24300+1del]

NM_001164508.2(NEB):c.24297_24300+1del

Genes:

NEB:nebulin [Gene - OMIM - HGNC]
RIF1:replication timing regulatory factor 1 [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

2q23.3

Genomic location:

Preferred name:

NM_001164508.2(NEB):c.24297_24300+1del

HGVS:

NC_000002.12:g.151497626_151497630del
NG_009382.2:g.241859_241863del
NG_017162.2:g.92726_92730del
NM_001164507.2:c.24297_24300+1del
NM_001164508.2:c.24297_24300+1delMANE SELECT
NM_001271208.2:c.24402_24405+1del
NM_004543.5:c.18826-1261_18826-1257del
LRG_202:g.241859_241863del
NC_000002.11:g.152354139_152354143del
NC_000002.11:g.152354140_152354144del

Molecular consequence:

NM_004543.5:c.18826-1261_18826-1257del - intron variant - [Sequence Ontology: SO:0001627]
NM_001164507.2:c.24297_24300+1del - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001164508.2:c.24297_24300+1del - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001271208.2:c.24402_24405+1del - 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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004325143	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Sep 20, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 16199547, 25205138, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004325143

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Sep 20, 2023)

germline

clinical testing

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

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

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]

PMID:: 25205138
PMCID:: PMC4295925

See all PubMed Citations (3)

Details of each submission

From Invitae, SCV004325143.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This variant results in the deletion of c.24402_24405+1del 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 not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with NEB-related conditions. 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Feb 20, 2024

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