NM_001164508.2(NEB):c.24639_24640del (p.Arg8214fs) AND Nemaline myopathy 2

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Jul 1, 2025
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:: RCV000670683.8

Allele description [Variation Report for NM_001164508.2(NEB):c.24639_24640del (p.Arg8214fs)]

NM_001164508.2(NEB):c.24639_24640del (p.Arg8214fs)

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.24639_24640del (p.Arg8214fs)

HGVS:

NC_000002.12:g.151493808_151493809del
NG_009382.2:g.245680_245681del
NM_001164507.2:c.24639_24640del
NM_001164508.2:c.24639_24640delMANE SELECT
NM_001271208.1:c.24744_24745del
NM_001271208.2:c.24744_24745del
NM_004543.5:c.19071_19072del
NP_001157979.2:p.Arg8214fs
NP_001157980.2:p.Arg8214fs
NP_001258137.2:p.Arg8249fs
NP_004534.3:p.Arg6358fs
LRG_202t1:c.24744_24745del
LRG_202:g.245680_245681del
NC_000002.11:g.152350321_152350322del
NC_000002.11:g.152350322_152350323del
NM_001271208.1:c.24744_24745delAA

Protein change:

R6358fs

Links:

dbSNP: rs1357811155

Molecular consequence:

NM_001164507.2:c.24639_24640del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001164508.2:c.24639_24640del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001271208.2:c.24744_24745del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_004543.5:c.19071_19072del - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Name:: Nemaline myopathy 2 (NEM2)
Synonyms:: 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
SCV000795569	Counsyl	no assertion criteria provided	Likely pathogenic (Nov 9, 2017)	unknown	clinical testing
SCV003498630	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 8, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 25205138, 28492532
SCV007524661	Natera, Inc.	criteria provided, single submitter (Natera Variant Classification Schema (03/2026))	Likely pathogenic (Jul 1, 2025)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000795569

Counsyl

no assertion criteria provided

Likely pathogenic
(Nov 9, 2017)

unknown

clinical testing

SCV003498630

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 8, 2024)

germline

clinical testing

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

SCV007524661

Natera, Inc.

criteria provided, single submitter

(Natera Variant Classification Schema (03/2026))

Likely pathogenic
(Jul 1, 2025)

germline

clinical testing

Citation Link

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
not provided	unknown	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. doi: 10.1038/s41436-019-0624-9..

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Counsyl, SCV000795569.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003498630.4

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

Description

This sequence change creates a premature translational stop signal (p.Arg8249Serfs*9) 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). This variant is present in population databases (no rsID available, gnomAD 0.01%). 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: 554958). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as 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

From Natera, Inc., SCV007524661.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

The c.24744_24745delAA variant in NEB is a frameshift variant predicted to shift the reading frame beginning at codon 8249 and leads to a stop codon 9 codons downstream. This variant is expected to result in nonsense mediated decay, truncation, or a dysfunctional protein product. This variant is rare in the general population with a frequency below the threshold expected for the associated phenotype(s). Given the available evidence, this variant is 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: Apr 4, 2026

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