rs868845088

Variant names:

• chr20-63349873-C-A
• NM_000744.7:c.1538G>T

Your query was ambiguous. Multiple possible variants found:

• chr20-63349873-C-A
• chr20-63349873-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000744.7(CHRNA4):​c.1538G>T​(p.Arg513Leu) 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 1,440,836 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 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)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CHRNA4 NM_000744.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.60

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.056113422).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNA4	NM_000744.7	c.1538G>T	p.Arg513Leu	missense_variant	Exon 5 of 6	ENST00000370263.9	NP_000735.1
CHRNA4	NM_001256573.2	c.1010G>T	p.Arg337Leu	missense_variant	Exon 5 of 6		NP_001243502.1
CHRNA4	NR_046317.2	n.1747G>T		non_coding_transcript_exon_variant	Exon 5 of 6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRNA4	ENST00000370263.9	c.1538G>T	p.Arg513Leu	missense_variant	Exon 5 of 6	1	NM_000744.7	ENSP00000359285.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.94e-7 AC: 1 AN: 1440836 Hom.: 0 Cov.: 83 AF XY: 0.00000140 AC XY: 1 AN XY: 713782

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: 0.0000119

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	0.021
DANN	Benign	0.35
DEOGEN2	Benign	0.21	T;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0089	N
LIST_S2	Benign	0.51	T;T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.056	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.090	N;.
PrimateAI	Benign	0.33	T
PROVEAN	Benign	1.1	N;.
REVEL	Benign	0.13
Sift	Benign	0.46	T;.
Sift4G	Benign	0.58	T;T
Polyphen		0.0	B;.
Vest4		0.086
MutPred		0.49		Loss of loop (P = 0.0603);.;
MVP		0.45
MPC		0.49
ClinPred		0.058	T
GERP RS		-2.6
Varity_R		0.050
gMVP		0.22

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: chr20-61981225;