8-27460470-A-G

Variant names:

• chr8-27460470-A-G
• rs1560344
• NM_000742.4:c.*1159T>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.*1159T>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 0.412 in 152,172 control chromosomes in the GnomAD database, including 13,784 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.41 (13770 hom., cov: 31)
  • Exomes 𝑓: 0.44 (14 hom.)
• Consequence: CHRNA2 NM_000742.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.183
• 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: 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=-0.91).
• BP6: Variant 8-27460470-A-G is Benign according to our data. Variant chr8-27460470-A-G is described in ClinVar as Benign. ClinVar VariationId is 362673.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.472 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.*1159T>C		3_prime_UTR	Exon 7 of 7	NP_000733.2	Q15822-1
	CHRNA2	NM_001282455.2		c.*1159T>C		3_prime_UTR	Exon 7 of 7	NP_001269384.1	Q15822-2
	CHRNA2	NM_001347705.2		c.*1159T>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.*1159T>C		3_prime_UTR	Exon 7 of 7	ENSP00000385026.1	Q15822-1
	CHRNA2	ENST00000520600.1	TSL:1	n.*106T>C		downstream_gene	N/A

Frequencies

GnomAD3 genomes AF: 0.412 AC: 62535 AN: 151896 Hom.: 13762 Cov.: 31

Gnomad AFR AF: 0.253

Gnomad AMI AF: 0.353

Gnomad AMR AF: 0.433

Gnomad ASJ AF: 0.645

Gnomad EAS AF: 0.352

Gnomad SAS AF: 0.412

Gnomad FIN AF: 0.530

Gnomad MID AF: 0.585

Gnomad NFE AF: 0.476

Gnomad OTH AF: 0.464

GnomAD4 exome AF: 0.436 AC: 68 AN: 156 Hom.: 14 Cov.: 0 AF XY: 0.434 AC XY: 53 AN XY: 122

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

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AF: 0.750 AC: 3 AN: 4

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

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.300 AC: 3 AN: 10

Middle Eastern (MID) AF: 0.250 AC: 1 AN: 4

European-Non Finnish (NFE) AF: 0.426 AC: 52 AN: 122

Other (OTH) AF: 0.700 AC: 7 AN: 10

GnomAD4 genome AF: 0.412 AC: 62571 AN: 152016 Hom.: 13770 Cov.: 31 AF XY: 0.413 AC XY: 30708 AN XY: 74308

African (AFR) AF: 0.253 AC: 10496 AN: 41456

American (AMR) AF: 0.433 AC: 6626 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.645 AC: 2241 AN: 3472

East Asian (EAS) AF: 0.352 AC: 1813 AN: 5144

South Asian (SAS) AF: 0.410 AC: 1975 AN: 4816

European-Finnish (FIN) AF: 0.530 AC: 5607 AN: 10586

Middle Eastern (MID) AF: 0.582 AC: 171 AN: 294

European-Non Finnish (NFE) AF: 0.476 AC: 32335 AN: 67936

Other (OTH) AF: 0.469 AC: 987 AN: 2106

Alfa AF: 0.451 Hom.: 25419

Bravo AF: 0.400

Asia WGS AF: 0.382 AC: 1326 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	-0.91
CADD	Benign	1.7
DANN	Benign	0.63
PhyloP100		0.18
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: rs1560344; hg19: chr8-27317987;