8-27468104-A-G

Variant names:

• chr8-27468104-A-G
• rs891400
• NM_000742.4:c.340-766T>C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 1 publications found

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]

CHRNA2 Gene-Disease associations (from GenCC):

• autosomal dominant nocturnal frontal lobe epilepsy 4

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: G2P, Illumina, Labcorp Genetics (formerly Invitae)
• autosomal dominant nocturnal frontal lobe epilepsy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial sleep-related hypermotor epilepsy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• benign familial infantile epilepsy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• epilepsy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000742.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNA2	NM_000742.4	MANE Select	c.340-766T>C		intron	N/A	NP_000733.2	Q15822-1
	CHRNA2	NM_001282455.2		c.295-766T>C		intron	N/A	NP_001269384.1	Q15822-2
	CHRNA2	NM_001347705.2		c.-133-766T>C		intron	N/A	NP_001334634.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNA2	ENST00000407991.3	TSL:5 MANE Select	c.340-766T>C		intron	N/A	ENSP00000385026.1	Q15822-1
	CHRNA2	ENST00000523695.5	TSL:1	n.340-766T>C		intron	N/A	ENSP00000430612.1	E5RJ54
	CHRNA2	ENST00000240132.7	TSL:2	c.295-766T>C		intron	N/A	ENSP00000240132.2	Q15822-2

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

African (AFR) AF: 0.222 AC: 9216 AN: 41498

American (AMR) AF: 0.187 AC: 2853 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0550 AC: 191 AN: 3470

East Asian (EAS) AF: 0.443 AC: 2291 AN: 5176

South Asian (SAS) AF: 0.149 AC: 717 AN: 4822

European-Finnish (FIN) AF: 0.165 AC: 1745 AN: 10590

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.134 AC: 9086 AN: 67998

Other (OTH) AF: 0.146 AC: 308 AN: 2110

Alfa AF: 0.154 Hom.: 269

Bravo AF: 0.178

Asia WGS AF: 0.270 AC: 937 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	15
DANN	Benign	0.82
PhyloP100		0.85
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs891400; hg19: chr8-27325621;