NM_001164508.2(NEB):c.24588C>G (p.Tyr8196Ter) AND Nemaline myopathy 2

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Feb 6, 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:: RCV000670685.16

Allele description [Variation Report for NM_001164508.2(NEB):c.24588C>G (p.Tyr8196Ter)]

NM_001164508.2(NEB):c.24588C>G (p.Tyr8196Ter)

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.24588C>G (p.Tyr8196Ter)

HGVS:

NC_000002.12:g.151493859G>C
NG_009382.2:g.245629C>G
NM_001164507.2:c.24588C>G
NM_001164508.2:c.24588C>GMANE SELECT
NM_001271208.2:c.24693C>G
NM_004543.5:c.19020C>G
NP_001157979.2:p.Tyr8196Ter
NP_001157980.2:p.Tyr8196Ter
NP_001258137.2:p.Tyr8231Ter
NP_004534.3:p.Tyr6340Ter
LRG_202t1:c.24693C>G
LRG_202:g.245629C>G
NC_000002.11:g.152350373G>C
NM_001271208.1:c.24693C>G
p.Tyr8196Ter

Protein change:

Y6340*

Links:

dbSNP: rs754272530

NCBI 1000 Genomes Browser:

rs754272530

Molecular consequence:

NM_001164507.2:c.24588C>G - nonsense - [Sequence Ontology: SO:0001587]
NM_001164508.2:c.24588C>G - nonsense - [Sequence Ontology: SO:0001587]
NM_001271208.2:c.24693C>G - nonsense - [Sequence Ontology: SO:0001587]
NM_004543.5:c.19020C>G - nonsense - [Sequence Ontology: SO:0001587]

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
SCV000795571	Counsyl	no assertion criteria provided	Likely pathogenic (Nov 9, 2017)	unknown	clinical testing
SCV000832909	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Feb 6, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 25205138, 29382405, 28492532
SCV001164419	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 3, 2018)	germline	research	PubMed (1) [See all records that cite this PMID]
SCV001760059	Genomics England Pilot Project, Genomics England	no assertion criteria provided (ACGS Guidelines, 2016)	Pathogenic	germline	clinical testing	Citation Link

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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	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing, research
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

Next-Generation Sequencing to Diagnose Muscular Dystrophy, Rhabdomyolysis, and HyperCKemia.

Wu L, Brady L, Shoffner J, Tarnopolsky MA.

Can J Neurol Sci. 2018 May;45(3):262-268. doi: 10.1017/cjn.2017.286. Epub 2018 Jan 31.

PubMed [citation]

PMID:: 29382405

See all PubMed Citations (4)

Details of each submission

From Counsyl, SCV000795571.2

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

#	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, SCV000832909.7

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

Description

This sequence change creates a premature translational stop signal (p.Tyr8231*) 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 (rs754272530, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with clinical features of nemaline myopathy (PMID: 29382405). This variant is also known as c.24588C>G (p.Tyr8196*). ClinVar contains an entry for this variant (Variation ID: 432817). 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 Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV001164419.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	PubMed (1)

Description

The heterozygous p.Tyr8196Ter variant in NEB was identified by our study in the compound heterozygous state, with a likely pathogenic variant, in one individual with nemaline myopathy. The presence of this variant in combination with a likely pathogenic variant and in an individual with nemaline myopathy increases the likelihood that the p.Tyr8196Ter variant is pathogenic. This variant has been identified in 0.005516% (5/90638) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs754272530). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This nonsense variant leads to a premature termination codon at position 8196, which is predicted to lead to a truncated or absent protein. Loss of function of the NEB gene is an established disease mechanism for autosomal recessive nemaline myopathy. In summary, this variant meets criteria to be classified as pathogenic for nemaline myopathy an autosomal recessive manner based on the predicted impact of the variant and occurrence with a likely pathogenic in an individual with nemaline myopathy. ACMG/AMP Criteria applied: PM2, PVS1, PM3_Supporting (Richards 2015).

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

From Genomics England Pilot Project, Genomics England, SCV001760059.1

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

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

Last Updated: May 16, 2025

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