NM_005876.5(SPEG):c.8872C>T (p.Arg2958Ter) AND Myopathy, centronuclear, 5

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jan 25, 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:: RCV002810024.2

Allele description [Variation Report for NM_005876.5(SPEG):c.8872C>T (p.Arg2958Ter)]

NM_005876.5(SPEG):c.8872C>T (p.Arg2958Ter)

Genes:

ASIC4-AS1:ASIC4 antisense RNA 1 [Gene - HGNC]
SPEG:striated muscle enriched protein kinase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2q35

Genomic location:

Preferred name:

NM_005876.5(SPEG):c.8872C>T (p.Arg2958Ter)

Other names:

NM_005876.5:c.8872C>T

HGVS:

NC_000002.12:g.219489890C>T
NG_051022.1:g.60676C>T
NM_005876.5:c.8872C>TMANE SELECT
NP_005867.3:p.Arg2958Ter
NC_000002.11:g.220354612C>T

Protein change:

R2958*

Links:

dbSNP: rs764429761

NCBI 1000 Genomes Browser:

rs764429761

Molecular consequence:

NM_005876.5:c.8872C>T - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:: Myopathy, centronuclear, 5 (CNM5)
Identifiers:: MONDO: MONDO:0014418; MedGen: C4014814; Orphanet: 169186; OMIM: 615959

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003761226	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 25, 2023)	germline	curation	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003761226

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jan 25, 2023)

germline

curation

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

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	curation

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

Details of each submission

From Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV003761226.1

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

Description

The homozygous p.Arg2958Ter variant in SPEG was identified by our study in one individual with congenital myopathy. The p.Arg2958Ter variant in SPEG has been reported in two siblings with congenital myopathy and segregated with disease in these two affected relatives from this one family (PMID: 34742623), but has been identified in 0.003% (1/29644) of South Asian chromosomes by the Genome Aggregation Consortium (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs764429761). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This nonsense variant leads to a premature termination codon at position 2958, which is predicted to lead to a truncated or absent protein. Loss of function of the SPEG gene is an established disease mechanism in autosomal recessive centronuclear myopathy 5. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive centronuclear myopathy 5. ACMG/AMP Criteria applied: PVS1, PM2_Supporting, PM3_Supporting (Richards 2015).

#	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: May 16, 2025

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