8-27463370-C-G

Variant names:

• chr8-27463370-C-G
• NM_000742.4:c.1073G>C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000742.4(CHRNA2):​c.1073G>C​(p.Ser358Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CHRNA2 NM_000742.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.08

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27509958).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNA2	NM_000742.4	c.1073G>C	p.Ser358Thr	missense_variant	Exon 6 of 7	ENST00000407991.3	NP_000733.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRNA2	ENST00000407991.3	c.1073G>C	p.Ser358Thr	missense_variant	Exon 6 of 7	5	NM_000742.4	ENSP00000385026.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.078	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	21
DANN	Benign	0.92
DEOGEN2	Benign	0.30	T;.;.
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.023
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.51	T;T;T
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.28	T;T;T
MetaSVM	Benign	-0.41	T
MutationAssessor	Benign	1.9	M;.;.
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.1	N;.;N
REVEL	Benign	0.26
Sift	Benign	0.45	T;.;T
Sift4G	Benign	0.35	T;T;T
Polyphen		0.0	B;.;.
Vest4		0.27
MutPred		0.37		Gain of catalytic residue at S358 (P = 0.0262);.;.;
MVP		0.84
MPC		0.20
ClinPred		0.51	D
GERP RS		4.0
Varity_R		0.15
gMVP		0.40

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-27320887;