8-27459756-T-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_000742.4(CHRNA2):c.*1873A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00367 in 154,206 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0037 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0015 (0 hom.)
• Consequence: CHRNA2 NM_000742.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0840

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 8-27459756-T-C is Benign according to our data. Variant chr8-27459756-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 369609.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 558 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHRNA2	NM_000742.4	c.*1873A>G		3_prime_UTR_variant	7/7	ENST00000407991.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHRNA2	ENST00000407991.3	c.*1873A>G		3_prime_UTR_variant	7/7	5	NM_000742.4	P2

Frequencies

GnomAD3 genomes AF: 0.00367 AC: 558 AN: 152128 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.0122

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00249

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00335

GnomAD4 exome AF: 0.00153 AC: 3 AN: 1960 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 992

Gnomad4 AFR exome AF: 0.0161

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000893

Gnomad4 OTH exome AF: 0.00769

GnomAD4 genome AF: 0.00370 AC: 563 AN: 152246 Hom.: 4 Cov.: 33 AF XY: 0.00365 AC XY: 272 AN XY: 74438

Gnomad4 AFR AF: 0.0123

Gnomad4 AMR AF: 0.00144

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00249

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00154 Hom.: 0

Bravo AF: 0.00388

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Sleep-related hypermotor epilepsy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	3.3
Dann	Benign	0.58

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs146191907; hg19: chr8-27317273;