NM_000742.4(CHRNA2):c.1105dup (p.Ala369fs) AND Autosomal dominant nocturnal frontal lobe epilepsy

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Mar 4, 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:: RCV003768122.2

Allele description [Variation Report for NM_000742.4(CHRNA2):c.1105dup (p.Ala369fs)]

NM_000742.4(CHRNA2):c.1105dup (p.Ala369fs)

Gene:

CHRNA2:cholinergic receptor nicotinic alpha 2 subunit [Gene - OMIM - HGNC]

Variant type:

Duplication

Cytogenetic location:

8p21.2

Genomic location:

Preferred name:

NM_000742.4(CHRNA2):c.1105dup (p.Ala369fs)

HGVS:

NC_000008.11:g.27463343dup
NG_015827.1:g.20959dup
NM_000742.4:c.1105dupMANE SELECT
NM_001282455.2:c.1060dup
NM_001347705.2:c.628dup
NM_001347706.2:c.628dup
NM_001347707.2:c.511dup
NM_001347708.2:c.511dup
NP_000733.2:p.Ala369fs
NP_001269384.1:p.Ala354fs
NP_001334634.1:p.Ala210fs
NP_001334635.1:p.Ala210fs
NP_001334636.1:p.Ala171fs
NP_001334637.1:p.Ala171fs
NC_000008.10:g.27320854_27320855insC
NC_000008.10:g.27320860dup
NM_000742.3:c.1105dupG

Protein change:

A171fs

Links:

dbSNP: rs757376257

NCBI 1000 Genomes Browser:

rs757376257

Molecular consequence:

NM_000742.4:c.1105dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001282455.2:c.1060dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001347705.2:c.628dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001347706.2:c.628dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001347707.2:c.511dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001347708.2:c.511dup - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Name:: Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE)
Identifiers:: MONDO: MONDO:0020300; MedGen: C3696898

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004623106	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Mar 4, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004623106

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Mar 4, 2023)

germline

clinical testing

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	clinical testing

Citations

PubMed

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 Labcorp Genetics (formerly Invitae), Labcorp, SCV004623106.1

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

Description

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. ClinVar contains an entry for this variant (Variation ID: 587981). This premature translational stop signal has been observed in at least one individual who was not affected with CHRNA2-related conditions (Invitae). This variant has not been reported in the literature in individuals affected with CHRNA2-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change creates a premature translational stop signal (p.Ala369Glyfs*84) in the CHRNA2 gene. It is expected to result in an absent or disrupted protein product. However, the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in CHRNA2 cause disease.

#	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: Oct 8, 2024

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