20-63350572-G-C

Position:

• chr20-63350572-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Strong

The NM_000744.7(CHRNA4):​c.839C>G​(p.Ser280Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S280L) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CHRNA4 NM_000744.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.79

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]

CHRNA4 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.968

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHRNA4	NM_000744.7	c.839C>G	p.Ser280Cys	missense_variant	5/6	ENST00000370263.9	NP_000735.1
CHRNA4	NM_001256573.2	c.311C>G	p.Ser104Cys	missense_variant	5/6		NP_001243502.1
CHRNA4	NR_046317.2	n.1048C>G		non_coding_transcript_exon_variant	5/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHRNA4	ENST00000370263.9	c.839C>G	p.Ser280Cys	missense_variant	5/6	1	NM_000744.7	ENSP00000359285.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 100

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal dominant nocturnal frontal lobe epilepsy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 30, 2019

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. A different missense substitution at this codon (p.Ser280Phe) has been determined to be pathogenic (PMID: 22036597, 7550350). This suggests that the serine residue is critical for CHRNA4 protein function and that other missense substitutions at this position may also be pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with CHRNA4-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces serine with cysteine at codon 280 of the CHRNA4 protein (p.Ser280Cys). The serine residue is highly conserved and there is a moderate physicochemical difference between serine and cysteine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.87	D;.
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.84	T;D
M_CAP	Pathogenic	0.42	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Uncertain	0.41	D
MutationAssessor	Pathogenic	3.8	H;.
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-5.0	D;.
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.93
MutPred		0.89		Gain of sheet (P = 0.1208);.;
MVP		0.90
MPC		1.2
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.77
gMVP		0.94

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: rs121909580; hg19: chr20-61981924;