8-27461118-C-G

Variant names:

• chr8-27461118-C-G
• rs2292977
• NM_000742.4:c.*511G>C

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.*511G>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 0.836 in 182,446 control chromosomes in the GnomAD database, including 64,328 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.84 (54132 hom., cov: 32)
  • Exomes 𝑓: 0.81 (10196 hom.)
• Consequence: CHRNA2 NM_000742.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.21
• Publications: 8 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BP6: Variant 8-27461118-C-G is Benign according to our data. Variant chr8-27461118-C-G is described in ClinVar as Benign. ClinVar VariationId is 362686.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.869 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.*511G>C		3_prime_UTR	Exon 7 of 7	NP_000733.2	Q15822-1
	CHRNA2	NM_001282455.2		c.*511G>C		3_prime_UTR	Exon 7 of 7	NP_001269384.1	Q15822-2
	CHRNA2	NM_001347705.2		c.*511G>C		3_prime_UTR	Exon 7 of 7	NP_001334634.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNA2	ENST00000407991.3	TSL:5 MANE Select	c.*511G>C		3_prime_UTR	Exon 7 of 7	ENSP00000385026.1	Q15822-1
	CHRNA2	ENST00000520600.1	TSL:1	n.926G>C		non_coding_transcript_exon	Exon 2 of 2
	CHRNA2	ENST00000523695.5	TSL:1	n.*1503G>C		non_coding_transcript_exon	Exon 7 of 7	ENSP00000430612.1	E5RJ54

Frequencies

GnomAD3 genomes AF: 0.841 AC: 127779 AN: 152026 Hom.: 54091 Cov.: 32

Gnomad AFR AF: 0.876

Gnomad AMI AF: 0.878

Gnomad AMR AF: 0.808

Gnomad ASJ AF: 0.929

Gnomad EAS AF: 0.523

Gnomad SAS AF: 0.843

Gnomad FIN AF: 0.802

Gnomad MID AF: 0.940

Gnomad NFE AF: 0.850

Gnomad OTH AF: 0.863

GnomAD4 exome AF: 0.811 AC: 24564 AN: 30300 Hom.: 10196 Cov.: 0 AF XY: 0.815 AC XY: 13137 AN XY: 16110

African (AFR) AF: 0.864 AC: 836 AN: 968

American (AMR) AF: 0.817 AC: 2733 AN: 3344

Ashkenazi Jewish (ASJ) AF: 0.907 AC: 461 AN: 508

East Asian (EAS) AF: 0.471 AC: 1023 AN: 2170

South Asian (SAS) AF: 0.858 AC: 3233 AN: 3768

European-Finnish (FIN) AF: 0.794 AC: 743 AN: 936

Middle Eastern (MID) AF: 0.959 AC: 71 AN: 74

European-Non Finnish (NFE) AF: 0.834 AC: 14324 AN: 17172

Other (OTH) AF: 0.838 AC: 1140 AN: 1360

GnomAD4 genome AF: 0.840 AC: 127873 AN: 152146 Hom.: 54132 Cov.: 32 AF XY: 0.835 AC XY: 62125 AN XY: 74368

African (AFR) AF: 0.876 AC: 36370 AN: 41510

American (AMR) AF: 0.808 AC: 12353 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.929 AC: 3226 AN: 3472

East Asian (EAS) AF: 0.523 AC: 2692 AN: 5150

South Asian (SAS) AF: 0.841 AC: 4058 AN: 4824

European-Finnish (FIN) AF: 0.802 AC: 8487 AN: 10588

Middle Eastern (MID) AF: 0.935 AC: 275 AN: 294

European-Non Finnish (NFE) AF: 0.850 AC: 57785 AN: 67992

Other (OTH) AF: 0.865 AC: 1826 AN: 2112

Alfa AF: 0.809 Hom.: 2484

Bravo AF: 0.843

Asia WGS AF: 0.724 AC: 2519 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.49
DANN	Benign	0.63
PhyloP100		-1.2
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: rs2292977; hg19: chr8-27318635;