rs16969968

Variant summary

Our verdict is Benign. The variant received -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. 13/22 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 was made for transcript

Our verdict: Benign. The variant received -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 rank MANE Protein UniProt
CHRNA5NM_000745.4 linkc.1192G>A p.Asp398Asn missense_variant Exon 5 of 6 ENST00000299565.9 NP_000736.2 P30532Q6EWN4

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CHRNA5ENST00000299565.9 linkc.1192G>A p.Asp398Asn missense_variant Exon 5 of 6 1 NM_000745.4 ENSP00000299565.5 P30532

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
GnomAD2 exomes
AF:
0.264
AC:
66316
AN:
250966
AF XY:
0.276
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 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
AC:
1748
AN:
33476
Gnomad4 AMR exome
AF:
0.171
AC:
7663
AN:
44720
Gnomad4 ASJ exome
AF:
0.375
AC:
9800
AN:
26134
Gnomad4 EAS exome
AF:
0.0261
AC:
1035
AN:
39698
Gnomad4 SAS exome
AF:
0.239
AC:
20570
AN:
86246
Gnomad4 FIN exome
AF:
0.330
AC:
17593
AN:
53386
Gnomad4 NFE exome
AF:
0.335
AC:
372071
AN:
1111828
Gnomad4 Remaining exome
AF:
0.290
AC:
17536
AN:
60386
Heterozygous variant carriers
0
16542
33084
49625
66167
82709
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Exome Het
Exome Hom
Variant carriers
0
11516
23032
34548
46064
57580
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
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
AC:
0.0591918
AN:
0.0591918
Gnomad4 AMR
AF:
0.226
AC:
0.226161
AN:
0.226161
Gnomad4 ASJ
AF:
0.375
AC:
0.375216
AN:
0.375216
Gnomad4 EAS
AF:
0.0320
AC:
0.0320093
AN:
0.0320093
Gnomad4 SAS
AF:
0.222
AC:
0.221508
AN:
0.221508
Gnomad4 FIN
AF:
0.327
AC:
0.32693
AN:
0.32693
Gnomad4 NFE
AF:
0.347
AC:
0.346959
AN:
0.346959
Gnomad4 OTH
AF:
0.275
AC:
0.275095
AN:
0.275095
Heterozygous variant carriers
0
1317
2633
3950
5266
6583
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Genome Het
Genome Hom
Variant carriers
0
370
740
1110
1480
1850
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.304
Hom.:
35353
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
-
HLA Laboratory, Instituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas
Significance:Uncertain significance
Review Status:no assertion criteria provided
Collection Method:research

- -

Lung cancer susceptibility 2 Other:1
Jul 27, 2010
OMIM
Significance:risk factor
Review Status:no assertion criteria provided
Collection Method:literature only

- -

nicotine response - Toxicity Other:1
Mar 24, 2021
PharmGKB
Significance:drug response
Review Status:reviewed by expert panel
Collection Method:curation

PharmGKB 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
Jul 27, 2010
OMIM
Significance:risk factor
Review Status:no assertion criteria provided
Collection Method:literature only

- -

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
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
Mutation Taster
=74/26
polymorphism (auto)

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