rs78306886

chr20-63350051-C-T

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.1360G>A(p.Gly454Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000186 in 1,513,022 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict 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. G454D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00019 (0 hom.)
• Consequence: CHRNA4 NM_000744.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: -0.145

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=0.015547037).
• BP6: Variant 20-63350051-C-T is Benign according to our data. Variant chr20-63350051-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 204998.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000151 (23/152260) while in subpopulation SAS AF= 0.00083 (4/4820). AF 95% confidence interval is 0.000283. There are 0 homozygotes in gnomad4. There are 13 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 23 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHRNA4	NM_000744.7	c.1360G>A	p.Gly454Ser	missense_variant	5/6	ENST00000370263.9
CHRNA4	NM_001256573.2	c.832G>A	p.Gly278Ser	missense_variant	5/6
CHRNA4	NR_046317.2	n.1569G>A		non_coding_transcript_exon_variant	5/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHRNA4	ENST00000370263.9	c.1360G>A	p.Gly454Ser	missense_variant	5/6	1	NM_000744.7	P1

Frequencies

GnomAD3 genomes AF: 0.000151 AC: 23 AN: 152142 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000331 AC: 44 AN: 132892 Hom.: 0 AF XY: 0.000398 AC XY: 28 AN XY: 70436

Gnomad AFR exome AF: 0.000112

Gnomad AMR exome AF: 0.000188

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000863

Gnomad FIN exome AF: 0.000252

Gnomad NFE exome AF: 0.000423

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000190 AC: 258 AN: 1360762 Hom.: 0 Cov.: 83 AF XY: 0.000222 AC XY: 148 AN XY: 665902

Gnomad4 AFR exome AF: 0.0000323

Gnomad4 AMR exome AF: 0.000220

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000422

Gnomad4 FIN exome AF: 0.000265

Gnomad4 NFE exome AF: 0.000187

Gnomad4 OTH exome AF: 0.000160

GnomAD4 genome AF: 0.000151 AC: 23 AN: 152260 Hom.: 0 Cov.: 33 AF XY: 0.000175 AC XY: 13 AN XY: 74442

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000830

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000348 Hom.: 0

Bravo AF: 0.000204

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.000265 AC: 31

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 03, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 05, 2020	This variant is associated with the following publications: (PMID: 22873564, 19628475) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	CHRNA4: BP4, BS2 -

Autosomal dominant nocturnal frontal lobe epilepsy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 18, 2024

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 10, 2018

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.52
Cadd	Benign	0.047
Dann	Benign	0.40
DEOGEN2	Benign	0.20	T;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.015	N
LIST_S2	Benign	0.52	T;T
M_CAP	Benign	0.075	D
MetaRNN	Benign	0.016	T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	-0.30	N;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.060	N;.
REVEL	Benign	0.16
Sift	Benign	1.0	T;.
Sift4G	Benign	0.36	T;T
Polyphen		0.0010	B;.
Vest4		0.064
MVP		0.45
MPC		0.40
ClinPred		0.0061	T
GERP RS		-0.19
Varity_R		0.049
gMVP		0.23

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: rs78306886; hg19: chr20-61981403;