NM_001164508.2(NEB):c.22814_22818del (p.Glu7605fs) AND Nemaline myopathy 2

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Feb 12, 2022
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:: RCV003016610.2

Allele description [Variation Report for NM_001164508.2(NEB):c.22814_22818del (p.Glu7605fs)]

NM_001164508.2(NEB):c.22814_22818del (p.Glu7605fs)

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.22814_22818del (p.Glu7605fs)

HGVS:

NC_000002.12:g.151516550_151516554del
NG_009382.2:g.222938_222942del
NG_017162.2:g.111650_111654del
NM_001164507.2:c.22814_22818del
NM_001164508.2:c.22814_22818delMANE SELECT
NM_001271208.2:c.22919_22923del
NM_004543.5:c.17711_17715del
NP_001157979.2:p.Glu7605fs
NP_001157980.2:p.Glu7605fs
NP_001258137.1:p.Glu7640Valfs
NP_001258137.2:p.Glu7640fs
NP_004534.2:p.Glu5904Valfs
NP_004534.3:p.Glu5904fs
LRG_202t1:c.22915_22919del
LRG_202:g.222938_222942del
LRG_202p1:p.Glu7640Valfs
NC_000002.11:g.152373060_152373064del
NC_000002.11:g.152373064_152373068del
NM_001271208.1:c.22915_22919delAAAGA
NM_004543.3:c.17707_17711delAAAGA

Protein change:

E5904fs

Molecular consequence:

NM_001164507.2:c.22814_22818del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001164508.2:c.22814_22818del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001271208.2:c.22919_22923del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_004543.5:c.17711_17715del - frameshift variant - [Sequence Ontology: SO:0001589]

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
SCV003312935	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Feb 12, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 25205138, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003312935

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Feb 12, 2022)

germline

clinical testing

PubMed (2)
[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

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

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Invitae, SCV003312935.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This variant has not been reported in the literature in individuals affected with NEB-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Glu7640Valfs*2) 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).

#	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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