rs200010568

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 4P and 9B. PP3_StrongBP6BS1BS2

The ENST00000370263.9(CHRNA4):​c.358C>T​(p.Arg120Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000714 in 1,611,702 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. R120R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 30)
Exomes 𝑓: 0.000073 ( 0 hom. )

Consequence

CHRNA4
ENST00000370263.9 missense

Scores

4
9
5

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 0.550
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 Likely_benign. Variant got -5 ACMG points.

PP3
MetaRNN computational evidence supports a deleterious effect, 0.942
BP6
Variant 20-63356000-G-A is Benign according to our data. Variant chr20-63356000-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 205046.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0000529 (8/151178) while in subpopulation NFE AF= 0.000103 (7/67814). AF 95% confidence interval is 0.0000478. There are 0 homozygotes in gnomad4. There are 4 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.
BS2
High AC in GnomAd4 at 8 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CHRNA4NM_000744.7 linkuse as main transcriptc.358C>T p.Arg120Trp missense_variant 4/6 ENST00000370263.9 NP_000735.1
CHRNA4NM_001256573.2 linkuse as main transcriptc.-189C>T 5_prime_UTR_variant 4/6 NP_001243502.1
CHRNA4NR_046317.2 linkuse as main transcriptn.567C>T non_coding_transcript_exon_variant 4/6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CHRNA4ENST00000370263.9 linkuse as main transcriptc.358C>T p.Arg120Trp missense_variant 4/61 NM_000744.7 ENSP00000359285 P1P43681-1

Frequencies

GnomAD3 genomes
AF:
0.0000529
AC:
8
AN:
151178
Hom.:
0
Cov.:
30
show subpopulations
Gnomad AFR
AF:
0.0000244
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000103
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000640
AC:
16
AN:
249822
Hom.:
0
AF XY:
0.0000885
AC XY:
12
AN XY:
135592
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000163
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000977
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000733
AC:
107
AN:
1460524
Hom.:
0
Cov.:
33
AF XY:
0.0000702
AC XY:
51
AN XY:
726578
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000928
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000872
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000529
AC:
8
AN:
151178
Hom.:
0
Cov.:
30
AF XY:
0.0000542
AC XY:
4
AN XY:
73772
show subpopulations
Gnomad4 AFR
AF:
0.0000244
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000103
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000579
Hom.:
0
Bravo
AF:
0.0000302
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.0000662
AC:
8

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Autosomal dominant nocturnal frontal lobe epilepsy 1;C1861063:Tobacco addiction, susceptibility to Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsOct 31, 2018- -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxFeb 20, 2020In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Autosomal dominant nocturnal frontal lobe epilepsy Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpNov 24, 2023- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.30
BayesDel_addAF
Benign
-0.032
T
BayesDel_noAF
Uncertain
-0.020
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.76
D
Eigen
Uncertain
0.22
Eigen_PC
Benign
0.031
FATHMM_MKL
Benign
0.70
D
LIST_S2
Uncertain
0.97
D
M_CAP
Pathogenic
0.62
D
MetaRNN
Pathogenic
0.94
D
MetaSVM
Uncertain
0.19
D
MutationTaster
Benign
1.0
D
PrimateAI
Pathogenic
0.83
D
PROVEAN
Uncertain
-3.4
D
REVEL
Pathogenic
0.66
Sift
Uncertain
0.011
D
Sift4G
Uncertain
0.020
D
Polyphen
1.0
D
Vest4
0.85
MVP
0.84
MPC
1.2
ClinPred
0.93
D
GERP RS
-2.6
Varity_R
0.17
gMVP
0.83

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: rs200010568; hg19: chr20-61987352; COSMIC: COSV105921832; COSMIC: COSV105921832; API