rs78306886

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

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. 16/21 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

Scores

19

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: -0.145
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

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. Median coverage is 33. This position pass quality control queck.
BS2
High AC in GnomAd4 at 23 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CHRNA4NM_000744.7 linkuse as main transcriptc.1360G>A p.Gly454Ser missense_variant 5/6 ENST00000370263.9
CHRNA4NM_001256573.2 linkuse as main transcriptc.832G>A p.Gly278Ser missense_variant 5/6
CHRNA4NR_046317.2 linkuse as main transcriptn.1569G>A non_coding_transcript_exon_variant 5/6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CHRNA4ENST00000370263.9 linkuse as main transcriptc.1360G>A p.Gly454Ser missense_variant 5/61 NM_000744.7 P1P43681-1

Frequencies

GnomAD3 genomes
AF:
0.000151
AC:
23
AN:
152142
Hom.:
0
Cov.:
33
show subpopulations
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
show subpopulations
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
show subpopulations
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
show subpopulations
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:1Benign:4
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:1Benign:2
Uncertain significance, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesMar 03, 2020- -
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenOct 01, 2023CHRNA4: BP4, BS2 -
Likely benign, criteria provided, single submitterclinical testingGeneDxAug 05, 2020This variant is associated with the following publications: (PMID: 22873564, 19628475) -
Autosomal dominant nocturnal frontal lobe epilepsy Benign:1
Likely benign, criteria provided, single submitterclinical testingInvitaeJan 18, 2024- -
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsJul 10, 2018This 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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs78306886; hg19: chr20-61981403; API