rs111286066

Positions:

• chr20-63349889-C-A
• chr20-63349889-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000744.7(CHRNA4):​c.1522G>T​(p.Gly508Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000694 in 1,440,338 control chromosomes in the GnomAD database, with no homozygous occurrence. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G508S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CHRNA4 NM_000744.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.163

Genes affected

CHRNA4 (HGNC:1958): (cholinergic receptor nicotinic alpha 4 subunit) This gene encodes a nicotinic acetylcholine receptor, which belongs to a superfamily of ligand-gated ion channels that play a role in fast signal transmission at synapses. These pentameric receptors can bind acetylcholine, which causes an extensive change in conformation that leads to the opening of an ion-conducting channel across the plasma membrane. This protein is an integral membrane receptor subunit that can interact with either nAChR beta-2 or nAChR beta-4 to form a functional receptor. Mutations in this gene cause nocturnal frontal lobe epilepsy type 1. Polymorphisms in this gene that provide protection against nicotine addiction have been described. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2012]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHRNA4	NM_000744.7	c.1522G>T	p.Gly508Cys	missense_variant	5/6	ENST00000370263.9
CHRNA4	NM_001256573.2	c.994G>T	p.Gly332Cys	missense_variant	5/6
CHRNA4	NR_046317.2	n.1731G>T		non_coding_transcript_exon_variant	5/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHRNA4	ENST00000370263.9	c.1522G>T	p.Gly508Cys	missense_variant	5/6	1	NM_000744.7	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.94e-7 AC: 1 AN: 1440338 Hom.: 0 Cov.: 83 AF XY: 0.00 AC XY: 0 AN XY: 713476

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000169

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.052	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	11
DANN	Benign	0.97
DEOGEN2	Benign	0.39	T;.
Eigen	Benign	-0.72
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.57	T;T
M_CAP	Pathogenic	0.61	D
MetaRNN	Uncertain	0.49	T;T
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Benign	1.4	L;.
MutationTaster	Benign	0.99	N
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.92	N;.
REVEL	Uncertain	0.36
Sift	Uncertain	0.0060	D;.
Sift4G	Uncertain	0.0060	D;D
Polyphen		0.98	D;.
Vest4		0.35
MutPred		0.43		Loss of loop (P = 0.0603);.;
MVP		0.80
MPC		1.2
ClinPred		0.39	T
GERP RS		-4.6
Varity_R		0.17
gMVP		0.38

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: rs111286066; hg19: chr20-61981241;