rs2292974

Variant names:

• chr8-27460874-C-T
• rs2292974
• NM_000742.4:c.*755G>A

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.*755G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.409 in 152,036 control chromosomes in the GnomAD database, including 13,540 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.41 (13526 hom., cov: 32)
  • Exomes 𝑓: 0.55 (14 hom.)
• Consequence: CHRNA2 NM_000742.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.204
• Publications: 11 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=-0.9).
• BP6: Variant 8-27460874-C-T is Benign according to our data. Variant chr8-27460874-C-T is described in ClinVar as Benign. ClinVar VariationId is 362682.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.464 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.*755G>A		3_prime_UTR	Exon 7 of 7	NP_000733.2	Q15822-1
	CHRNA2	NM_001282455.2		c.*755G>A		3_prime_UTR	Exon 7 of 7	NP_001269384.1	Q15822-2
	CHRNA2	NM_001347705.2		c.*755G>A		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.*755G>A		3_prime_UTR	Exon 7 of 7	ENSP00000385026.1	Q15822-1
	CHRNA2	ENST00000520600.1	TSL:1	n.1170G>A		non_coding_transcript_exon	Exon 2 of 2
	CHRNA2	ENST00000523695.5	TSL:1	n.*1747G>A		downstream_gene	N/A	ENSP00000430612.1	E5RJ54

Frequencies

GnomAD3 genomes AF: 0.409 AC: 62094 AN: 151826 Hom.: 13516 Cov.: 32

Gnomad AFR AF: 0.260

Gnomad AMI AF: 0.310

Gnomad AMR AF: 0.429

Gnomad ASJ AF: 0.633

Gnomad EAS AF: 0.352

Gnomad SAS AF: 0.412

Gnomad FIN AF: 0.529

Gnomad MID AF: 0.579

Gnomad NFE AF: 0.468

Gnomad OTH AF: 0.459

GnomAD4 exome AF: 0.554 AC: 51 AN: 92 Hom.: 14 Cov.: 0 AF XY: 0.567 AC XY: 34 AN XY: 60

African (AFR) AF: 0.00 AC: 0 AN: 2

American (AMR) AF: 0.250 AC: 1 AN: 4

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.500 AC: 2 AN: 4

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.500 AC: 2 AN: 4

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.608 AC: 45 AN: 74

Other (OTH) AF: 0.250 AC: 1 AN: 4

GnomAD4 genome AF: 0.409 AC: 62141 AN: 151944 Hom.: 13526 Cov.: 32 AF XY: 0.411 AC XY: 30488 AN XY: 74262

African (AFR) AF: 0.260 AC: 10766 AN: 41400

American (AMR) AF: 0.429 AC: 6552 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.633 AC: 2192 AN: 3464

East Asian (EAS) AF: 0.352 AC: 1815 AN: 5152

South Asian (SAS) AF: 0.410 AC: 1974 AN: 4816

European-Finnish (FIN) AF: 0.529 AC: 5588 AN: 10564

Middle Eastern (MID) AF: 0.575 AC: 169 AN: 294

European-Non Finnish (NFE) AF: 0.468 AC: 31828 AN: 67960

Other (OTH) AF: 0.463 AC: 974 AN: 2102

Alfa AF: 0.448 Hom.: 42826

Bravo AF: 0.396

Asia WGS AF: 0.380 AC: 1322 AN: 3478

ClinVar

ClinVar submissions as Germline

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	-0.90
CADD	Benign	1.5
DANN	Benign	0.42
PhyloP100		-0.20
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: rs2292974; hg19: chr8-27318391;