rs200200279

Positions:

• chr20-63349952-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000744.7(CHRNA4):​c.1459C>T​(p.Arg487Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000856 in 1,576,198 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R487Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000078 (2 hom.)
• Consequence: CHRNA4 NM_000744.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 0.887

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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.040718913).
• BP6: Variant 20-63349952-G-A is Benign according to our data. Variant chr20-63349952-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 420221.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000158 (24/152304) while in subpopulation EAS AF= 0.000968 (5/5166). AF 95% confidence interval is 0.000552. There are 0 homozygotes in gnomad4. There are 10 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 24 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHRNA4	NM_000744.7	c.1459C>T	p.Arg487Trp	missense_variant	5/6	ENST00000370263.9	NP_000735.1
CHRNA4	NM_001256573.2	c.931C>T	p.Arg311Trp	missense_variant	5/6		NP_001243502.1
CHRNA4	NR_046317.2	n.1668C>T		non_coding_transcript_exon_variant	5/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHRNA4	ENST00000370263.9	c.1459C>T	p.Arg487Trp	missense_variant	5/6	1	NM_000744.7	ENSP00000359285	P1

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 152186 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000966

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000155 AC: 30 AN: 193920 Hom.: 0 AF XY: 0.000161 AC XY: 17 AN XY: 105608

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000354

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000745

Gnomad SAS exome AF: 0.000271

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000119

Gnomad OTH exome AF: 0.000203

GnomAD4 exome AF: 0.0000780 AC: 111 AN: 1423894 Hom.: 2 Cov.: 83 AF XY: 0.0000866 AC XY: 61 AN XY: 704128

Gnomad4 AFR exome AF: 0.0000305

Gnomad4 AMR exome AF: 0.000354

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00191

Gnomad4 SAS exome AF: 0.000134

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000732

Gnomad4 OTH exome AF: 0.0000682

GnomAD4 genome AF: 0.000158 AC: 24 AN: 152304 Hom.: 0 Cov.: 33 AF XY: 0.000134 AC XY: 10 AN XY: 74468

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000914

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000968

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.000147

ExAC AF: 0.000126 AC: 15

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 28, 2019	This variant is associated with the following publications: (PMID: 19628475, 22873564, 21107856, 24385388, 30054184) -

Autosomal dominant nocturnal frontal lobe epilepsy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 20, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CHRNA4 protein function. ClinVar contains an entry for this variant (Variation ID: 420221). This variant has not been reported in the literature in individuals affected with CHRNA4-related conditions. This variant is present in population databases (rs200200279, gnomAD 0.07%), and has an allele count higher than expected for a pathogenic variant. This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 487 of the CHRNA4 protein (p.Arg487Trp). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Uncertain	-0.070
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.43	T;.
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.43	N
LIST_S2	Uncertain	0.89	D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.041	T;T
MetaSVM	Benign	-0.69	T
MutationAssessor	Uncertain	2.2	M;.
MutationTaster	Benign	0.96	N
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-2.0	N;.
REVEL	Uncertain	0.51
Sift	Uncertain	0.024	D;.
Sift4G	Uncertain	0.033	D;D
Polyphen		0.30	B;.
Vest4		0.37
MutPred		0.56		Loss of disorder (P = 8e-04);.;
MVP		0.81
MPC		0.44
ClinPred		0.067	T
GERP RS		3.8
Varity_R		0.13
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

LitVar

Other links and lift over

dbSNP: rs200200279; hg19: chr20-61981304;