rs2292975

Variant names:

• chr8-27460908-C-A
• rs2292975
• NM_000742.4:c.*721G>T

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.*721G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.408 in 152,236 control chromosomes in the GnomAD database, including 13,485 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.41 (13466 hom., cov: 32)
  • Exomes 𝑓: 0.47 (19 hom.)
• Consequence: CHRNA2 NM_000742.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.418
• Publications: 9 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=-0.87).
• BP6: Variant 8-27460908-C-A is Benign according to our data. Variant chr8-27460908-C-A is described in ClinVar as Benign. ClinVar VariationId is 362683.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.*721G>T		3_prime_UTR	Exon 7 of 7	NP_000733.2	Q15822-1
	CHRNA2	NM_001282455.2		c.*721G>T		3_prime_UTR	Exon 7 of 7	NP_001269384.1	Q15822-2
	CHRNA2	NM_001347705.2		c.*721G>T		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.*721G>T		3_prime_UTR	Exon 7 of 7	ENSP00000385026.1	Q15822-1
	CHRNA2	ENST00000520600.1	TSL:1	n.1136G>T		non_coding_transcript_exon	Exon 2 of 2
	CHRNA2	ENST00000523695.5	TSL:1	n.*1713G>T		downstream_gene	N/A	ENSP00000430612.1	E5RJ54

Frequencies

GnomAD3 genomes AF: 0.408 AC: 61976 AN: 151952 Hom.: 13456 Cov.: 32

Gnomad AFR AF: 0.259

Gnomad AMI AF: 0.310

Gnomad AMR AF: 0.428

Gnomad ASJ AF: 0.633

Gnomad EAS AF: 0.346

Gnomad SAS AF: 0.411

Gnomad FIN AF: 0.521

Gnomad MID AF: 0.579

Gnomad NFE AF: 0.468

Gnomad OTH AF: 0.458

GnomAD4 exome AF: 0.470 AC: 78 AN: 166 Hom.: 19 Cov.: 0 AF XY: 0.446 AC XY: 50 AN XY: 112

African (AFR) AC: 0 AN: 0

American (AMR) AF: 0.500 AC: 2 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: 0.357 AC: 5 AN: 14

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.464 AC: 65 AN: 140

Other (OTH) AF: 1.00 AC: 4 AN: 4

GnomAD4 genome AF: 0.408 AC: 62023 AN: 152070 Hom.: 13466 Cov.: 32 AF XY: 0.409 AC XY: 30417 AN XY: 74324

African (AFR) AF: 0.260 AC: 10767 AN: 41476

American (AMR) AF: 0.428 AC: 6546 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.633 AC: 2194 AN: 3468

East Asian (EAS) AF: 0.346 AC: 1785 AN: 5158

South Asian (SAS) AF: 0.409 AC: 1972 AN: 4818

European-Finnish (FIN) AF: 0.521 AC: 5513 AN: 10576

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

European-Non Finnish (NFE) AF: 0.468 AC: 31816 AN: 67974

Other (OTH) AF: 0.463 AC: 978 AN: 2112

Alfa AF: 0.453 Hom.: 23604

Bravo AF: 0.396

Asia WGS AF: 0.376 AC: 1307 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	-0.87
CADD	Benign	6.4
DANN	Benign	0.74
PhyloP100		0.42
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: rs2292975; hg19: chr8-27318425;