NM_001164508.2(NEB):c.6076-1G>T AND Nemaline myopathy 2

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Nov 15, 2022
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:: RCV000668960.8

Allele description [Variation Report for NM_001164508.2(NEB):c.6076-1G>T]

NM_001164508.2(NEB):c.6076-1G>T

Gene:

NEB:nebulin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2q23.3

Genomic location:

Preferred name:

NM_001164508.2(NEB):c.6076-1G>T

HGVS:

NC_000002.12:g.151658091C>A
NG_009382.2:g.81397G>T
NM_001164507.2:c.6076-1G>T
NM_001164508.2:c.6076-1G>TMANE SELECT
NM_001271208.2:c.6076-1G>T
NM_004543.5:c.6076-1G>T
LRG_202t1:c.6076-1G>T
LRG_202:g.81397G>T
NC_000002.11:g.152514605C>A
NM_001271208.1:c.6076-1G>T

Links:

dbSNP: rs1553469502

NCBI 1000 Genomes Browser:

rs1553469502

Molecular consequence:

NM_001164507.2:c.6076-1G>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001164508.2:c.6076-1G>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001271208.2:c.6076-1G>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_004543.5:c.6076-1G>T - splice acceptor variant - [Sequence Ontology: SO:0001574]

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
SCV000793645	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Likely pathogenic (Aug 22, 2017)	unknown	clinical testing	Citation Link,
SCV001204195	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 15, 2022)	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

SCV000793645

Counsyl

criteria provided, single submitter

(Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))

Likely pathogenic
(Aug 22, 2017)

unknown

clinical testing

Citation Link,

SCV001204195

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Nov 15, 2022)

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
not provided	unknown	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 Counsyl, SCV000793645.1

#	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	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Invitae, SCV001204195.5

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

Description

Disruption of this splice site has been observed in individual(s) with clinical features of NEB-related conditions (Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. 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 disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 553493). This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 47 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).

#	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 28, 2024

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