8-27464080-G-C

Variant names:

• chr8-27464080-G-C
• rs3735757
• NM_000742.4:c.450-87C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000742.4(CHRNA2):​c.450-87C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.844 in 1,517,462 control chromosomes in the GnomAD database, including 543,356 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.82 (51568 hom., cov: 31)
  • Exomes 𝑓: 0.85 (491788 hom.)
• Consequence: CHRNA2 NM_000742.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.02
• Publications: 10 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: Labcorp Genetics (formerly Invitae), Illumina, G2P
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BP6: Variant 8-27464080-G-C is Benign according to our data. Variant chr8-27464080-G-C is described in ClinVar as Benign. ClinVar VariationId is 670757.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.853 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.450-87C>G		intron	N/A	NP_000733.2	Q15822-1
	CHRNA2	NM_001282455.2		c.405-87C>G		intron	N/A	NP_001269384.1	Q15822-2
	CHRNA2	NM_001347705.2		c.-23-92C>G		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.450-87C>G		intron	N/A	ENSP00000385026.1	Q15822-1
	CHRNA2	ENST00000520600.1	TSL:1	n.290-2326C>G		intron	N/A
	CHRNA2	ENST00000523695.5	TSL:1	n.450-220C>G		intron	N/A	ENSP00000430612.1	E5RJ54

Frequencies

GnomAD3 genomes AF: 0.821 AC: 124736 AN: 151988 Hom.: 51536 Cov.: 31

Gnomad AFR AF: 0.776

Gnomad AMI AF: 0.877

Gnomad AMR AF: 0.808

Gnomad ASJ AF: 0.935

Gnomad EAS AF: 0.555

Gnomad SAS AF: 0.850

Gnomad FIN AF: 0.836

Gnomad MID AF: 0.937

Gnomad NFE AF: 0.859

Gnomad OTH AF: 0.846

GnomAD4 exome AF: 0.847 AC: 1156463 AN: 1365356 Hom.: 491788 AF XY: 0.848 AC XY: 576511 AN XY: 679882

African (AFR) AF: 0.776 AC: 24173 AN: 31156

American (AMR) AF: 0.809 AC: 31342 AN: 38762

Ashkenazi Jewish (ASJ) AF: 0.925 AC: 23266 AN: 25158

East Asian (EAS) AF: 0.573 AC: 21269 AN: 37118

South Asian (SAS) AF: 0.868 AC: 70581 AN: 81322

European-Finnish (FIN) AF: 0.836 AC: 42183 AN: 50462

Middle Eastern (MID) AF: 0.924 AC: 3788 AN: 4098

European-Non Finnish (NFE) AF: 0.857 AC: 891742 AN: 1040376

Other (OTH) AF: 0.846 AC: 48119 AN: 56904

GnomAD4 genome AF: 0.821 AC: 124820 AN: 152106 Hom.: 51568 Cov.: 31 AF XY: 0.818 AC XY: 60823 AN XY: 74358

African (AFR) AF: 0.775 AC: 32157 AN: 41470

American (AMR) AF: 0.808 AC: 12345 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.935 AC: 3248 AN: 3472

East Asian (EAS) AF: 0.554 AC: 2857 AN: 5154

South Asian (SAS) AF: 0.849 AC: 4096 AN: 4826

European-Finnish (FIN) AF: 0.836 AC: 8858 AN: 10602

Middle Eastern (MID) AF: 0.932 AC: 274 AN: 294

European-Non Finnish (NFE) AF: 0.859 AC: 58401 AN: 67990

Other (OTH) AF: 0.847 AC: 1784 AN: 2106

Alfa AF: 0.811 Hom.: 2556

Bravo AF: 0.817

Asia WGS AF: 0.716 AC: 2490 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Autosomal dominant nocturnal frontal lobe epilepsy 4 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.81
DANN	Benign	0.56
PhyloP100		-2.0
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: rs3735757; hg19: chr8-27321597; COSMIC: COSV53560442; COSMIC: COSV53560442;