NM_000742.4:c.*1809T>C

Variant names:

• chr8-27459820-A-G
• rs2280375
• ENST00000407991:c.*1809T>C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000742.4(CHRNA2):​c.*1809T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.857 in 152,306 control chromosomes in the GnomAD database, including 56,264 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.86 (56236 hom., cov: 32)
  • Exomes 𝑓: 0.83 (28 hom.)
• Consequence: CHRNA2 NM_000742.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.83

Genes affected

CHRNA2 (HGNC:1956): (cholinergic receptor nicotinic alpha 2 subunit) Nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels formed by a pentameric arrangement of alpha and beta subunits to create distinct muscle and neuronal receptors. Neuronal receptors are found throughout the peripheral and central nervous system where they are involved in fast synaptic transmission. This gene encodes an alpha subunit that is widely expressed in the brain. The proposed structure for nAChR subunits is a conserved N-terminal extracellular domain followed by three conserved transmembrane domains, a variable cytoplasmic loop, a fourth conserved transmembrane domain, and a short C-terminal extracellular region. Mutations in this gene cause autosomal dominant nocturnal frontal lobe epilepsy type 4. Single nucleotide polymorphisms (SNPs) in this gene have been associated with nicotine dependence. [provided by RefSeq, Nov 2009]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.99).
• BP6: Variant 8-27459820-A-G is Benign according to our data. Variant chr8-27459820-A-G is described in ClinVar as [Benign]. Clinvar id is 362664.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.888 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNA2	NM_000742.4	c.*1809T>C		3_prime_UTR_variant	Exon 7 of 7	ENST00000407991.3	NP_000733.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRNA2	ENST00000407991	c.*1809T>C		3_prime_UTR_variant	Exon 7 of 7	5	NM_000742.4	ENSP00000385026.1

Frequencies

GnomAD3 genomes AF: 0.857 AC: 130373 AN: 152100 Hom.: 56189 Cov.: 32

Gnomad AFR AF: 0.896

Gnomad AMI AF: 0.911

Gnomad AMR AF: 0.821

Gnomad ASJ AF: 0.934

Gnomad EAS AF: 0.580

Gnomad SAS AF: 0.850

Gnomad FIN AF: 0.836

Gnomad MID AF: 0.946

Gnomad NFE AF: 0.861

Gnomad OTH AF: 0.875

GnomAD4 exome AF: 0.826 AC: 71 AN: 86 Hom.: 28 Cov.: 0 AF XY: 0.875 AC XY: 42 AN XY: 48

Gnomad4 AMR exome AF: 0.750

Gnomad4 ASJ exome AF: 0.500

Gnomad4 EAS exome AF: 0.750

Gnomad4 FIN exome AF: 0.800

Gnomad4 NFE exome AF: 0.833

Gnomad4 OTH exome AF: 1.00

GnomAD4 genome AF: 0.857 AC: 130474 AN: 152220 Hom.: 56236 Cov.: 32 AF XY: 0.853 AC XY: 63453 AN XY: 74412

Gnomad4 AFR AF: 0.896

Gnomad4 AMR AF: 0.821

Gnomad4 ASJ AF: 0.934

Gnomad4 EAS AF: 0.580

Gnomad4 SAS AF: 0.848

Gnomad4 FIN AF: 0.836

Gnomad4 NFE AF: 0.861

Gnomad4 OTH AF: 0.877

Alfa AF: 0.860 Hom.: 115012

Bravo AF: 0.859

Asia WGS AF: 0.743 AC: 2586 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Autosomal dominant nocturnal frontal lobe epilepsy 4 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	0.032
DANN	Benign	0.34

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2280375; hg19: chr8-27317337;