8-27468104-A-G

Position:

• chr8-27468104-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000742.4(CHRNA2):​c.340-766T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.174 in 152,158 control chromosomes in the GnomAD database, including 2,672 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.17 (2672 hom., cov: 32)
• Consequence: CHRNA2 NM_000742.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.848

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.428 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHRNA2	NM_000742.4	c.340-766T>C		intron_variant		ENST00000407991.3	NP_000733.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHRNA2	ENST00000407991.3	c.340-766T>C		intron_variant		5	NM_000742.4	ENSP00000385026	P2

Frequencies

GnomAD3 genomes AF: 0.174 AC: 26504 AN: 152040 Hom.: 2665 Cov.: 32

Gnomad AFR AF: 0.222

Gnomad AMI AF: 0.126

Gnomad AMR AF: 0.187

Gnomad ASJ AF: 0.0550

Gnomad EAS AF: 0.443

Gnomad SAS AF: 0.148

Gnomad FIN AF: 0.165

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.134

Gnomad OTH AF: 0.147

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.174 AC: 26542 AN: 152158 Hom.: 2672 Cov.: 32 AF XY: 0.177 AC XY: 13202 AN XY: 74400

Gnomad4 AFR AF: 0.222

Gnomad4 AMR AF: 0.187

Gnomad4 ASJ AF: 0.0550

Gnomad4 EAS AF: 0.443

Gnomad4 SAS AF: 0.149

Gnomad4 FIN AF: 0.165

Gnomad4 NFE AF: 0.134

Gnomad4 OTH AF: 0.146

Alfa AF: 0.151 Hom.: 253

Bravo AF: 0.178

Asia WGS AF: 0.270 AC: 937 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	15
DANN	Benign	0.82

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: rs891400; hg19: chr8-27325621;