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rs16969968

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000745.4(CHRNA5):c.1192G>A(p.Asp398Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.302 in 1,613,800 control chromosomes in the GnomAD database, including 79,728 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as drug response (★★★).

Frequency

Genomes: 𝑓 0.24 ( 5789 hom., cov: 32)
Exomes 𝑓: 0.31 ( 73939 hom. )

Consequence

CHRNA5
NM_000745.4 missense

Scores

1
2
15

Clinical Significance

drug response reviewed by expert panel U:1O:3

Conservation

PhyloP100: 7.89
Variant links:
Genes affected
CHRNA5 (HGNC:1959): (cholinergic receptor nicotinic alpha 5 subunit) The protein encoded by this gene is a nicotinic acetylcholine receptor subunit and a member of a superfamily of ligand-gated ion channels that mediate fast signal transmission at synapses. These receptors are thought to be heteropentamers composed of separate but similar subunits. Defects in this gene have been linked to susceptibility to lung cancer type 2 (LNCR2).[provided by RefSeq, Jun 2010]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.0011689961).
BA1
GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.343 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CHRNA5NM_000745.4 linkuse as main transcriptc.1192G>A p.Asp398Asn missense_variant 5/6 ENST00000299565.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CHRNA5ENST00000299565.9 linkuse as main transcriptc.1192G>A p.Asp398Asn missense_variant 5/61 NM_000745.4 P1
ENST00000567141.1 linkuse as main transcriptn.694C>T non_coding_transcript_exon_variant 1/1

Frequencies

GnomAD3 genomes
AF:
0.240
AC:
36562
AN:
152040
Hom.:
5789
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0594
Gnomad AMI
AF:
0.407
Gnomad AMR
AF:
0.226
Gnomad ASJ
AF:
0.375
Gnomad EAS
AF:
0.0317
Gnomad SAS
AF:
0.220
Gnomad FIN
AF:
0.327
Gnomad MID
AF:
0.408
Gnomad NFE
AF:
0.347
Gnomad OTH
AF:
0.277
GnomAD3 exomes
AF:
0.264
AC:
66316
AN:
250966
Hom.:
10589
AF XY:
0.276
AC XY:
37394
AN XY:
135724
show subpopulations
Gnomad AFR exome
AF:
0.0541
Gnomad AMR exome
AF:
0.162
Gnomad ASJ exome
AF:
0.376
Gnomad EAS exome
AF:
0.0314
Gnomad SAS exome
AF:
0.236
Gnomad FIN exome
AF:
0.321
Gnomad NFE exome
AF:
0.348
Gnomad OTH exome
AF:
0.295
GnomAD4 exome
AF:
0.308
AC:
450162
AN:
1461642
Hom.:
73939
Cov.:
38
AF XY:
0.308
AC XY:
223838
AN XY:
727150
show subpopulations
Gnomad4 AFR exome
AF:
0.0522
Gnomad4 AMR exome
AF:
0.171
Gnomad4 ASJ exome
AF:
0.375
Gnomad4 EAS exome
AF:
0.0261
Gnomad4 SAS exome
AF:
0.239
Gnomad4 FIN exome
AF:
0.330
Gnomad4 NFE exome
AF:
0.335
Gnomad4 OTH exome
AF:
0.290
GnomAD4 genome
AF:
0.240
AC:
36562
AN:
152158
Hom.:
5789
Cov.:
32
AF XY:
0.238
AC XY:
17675
AN XY:
74388
show subpopulations
Gnomad4 AFR
AF:
0.0592
Gnomad4 AMR
AF:
0.226
Gnomad4 ASJ
AF:
0.375
Gnomad4 EAS
AF:
0.0320
Gnomad4 SAS
AF:
0.222
Gnomad4 FIN
AF:
0.327
Gnomad4 NFE
AF:
0.347
Gnomad4 OTH
AF:
0.275
Alfa
AF:
0.320
Hom.:
18538
Bravo
AF:
0.224
TwinsUK
AF:
0.326
AC:
1210
ALSPAC
AF:
0.323
AC:
1246
ESP6500AA
AF:
0.0624
AC:
274
ESP6500EA
AF:
0.349
AC:
2993
ExAC
AF:
0.267
AC:
32420
Asia WGS
AF:
0.114
AC:
401
AN:
3478

ClinVar

Significance: drug response
Submissions summary: Uncertain:1Other:3
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Susceptibility to severe coronavirus disease (COVID-19) due to high levels of fibrinogen and C-reactive protein Uncertain:1
Uncertain significance, no assertion criteria providedresearchHLA Laboratory, Instituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas-- -
Lung cancer susceptibility 2 Other:1
risk factor, no assertion criteria providedliterature onlyOMIMJul 27, 2010- -
nicotine response - Toxicity Other:1
drug response, reviewed by expert panelcurationPharmGKBMar 24, 2021PharmGKB Level of Evidence 2B: Variants in Level 2B clinical annotations are not in PharmGKB’s Tier 1 VIPs. These clinical annotations describe variant-drug combinations with a moderate level of evidence supporting the association. For example, the association may be found in multiple cohorts, but there may be a minority of studies that do not support the majority assertion. Level 2B clinical annotations must be supported by at least two independent publications. Drug-variant association: Toxicity
Smoking as a quantitative trait locus 3 Other:1
risk factor, no assertion criteria providedliterature onlyOMIMJul 27, 2010- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.085
BayesDel_addAF
Benign
-0.54
T
BayesDel_noAF
Benign
-0.41
Cadd
Benign
18
Dann
Uncertain
0.98
DEOGEN2
Benign
0.24
T
Eigen
Benign
-0.46
Eigen_PC
Benign
-0.43
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Benign
0.79
T
MetaRNN
Benign
0.0012
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Uncertain
2.3
M
MutationTaster
Benign
0.00015
P;P
PrimateAI
Benign
0.38
T
PROVEAN
Benign
-1.4
N
REVEL
Benign
0.16
Sift
Benign
0.16
T
Sift4G
Benign
0.070
T
Polyphen
0.045
B
Vest4
0.071
MPC
0.21
ClinPred
0.060
T
GERP RS
3.9
Varity_R
0.041
gMVP
0.49

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: rs16969968; hg19: chr15-78882925; COSMIC: COSV55138088; COSMIC: COSV55138088; API