rs568479156

Positions:

• chr8-27469873-C-G
• chr8-27469873-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP3 BP6_Moderate BS2

The NM_000742.4(CHRNA2):​c.182G>C​(p.Arg61Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000821 in 1,461,870 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: CHRNA2 NM_000742.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.60

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]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.772
• BP6: Variant 8-27469873-C-G is Benign according to our data. Variant chr8-27469873-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 2080496.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAdExome4 at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHRNA2	NM_000742.4	c.182G>C	p.Arg61Pro	missense_variant	3/7	ENST00000407991.3	NP_000733.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHRNA2	ENST00000407991.3	c.182G>C	p.Arg61Pro	missense_variant	3/7	5	NM_000742.4	ENSP00000385026.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1461870 Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5 AN XY: 727234

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000899

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal dominant nocturnal frontal lobe epilepsy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 16, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.070
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D;.;.;.;.
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.93	D;D;D;D;T
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.77	D;D;D;D;D
MetaSVM	Uncertain	0.14	D
MutationAssessor	Pathogenic	3.6	H;.;H;.;.
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-4.3	D;.;D;D;D
REVEL	Uncertain	0.54
Sift	Uncertain	0.0010	D;.;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;.;D
Polyphen		0.99	D;.;.;.;.
Vest4		0.82
MutPred		0.73		Loss of MoRF binding (P = 0.0054);.;Loss of MoRF binding (P = 0.0054);Loss of MoRF binding (P = 0.0054);Loss of MoRF binding (P = 0.0054);
MVP		0.79
MPC		0.85
ClinPred		0.99	D
GERP RS		3.9
Varity_R		0.96
gMVP		0.84

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

Publications

LitVar

Other links and lift over

dbSNP: rs568479156; hg19: chr8-27327390;