rs16969968

Variant names:

Variant summary

Our verdict is The variant received -10 classification points (ACMG Germline Pathogenicity v2019): 0P and 10B. BA1BP4_Moderate

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 cumulative frequency of 0.302 (AC=486,724) in the gnomAD database across 1,613,800 control chromosomes, including 79,728 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.359. In-silico predictor (REVEL) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 7.89). Variant has been reported in ClinVar as Uncertain Significance (★★★). This exact variant is curated in the UniProt human variants database as Uncertain Significance, associated with Smoking as a quantitative trait locus 3 (sqtl3).

Frequency

Genomes: 𝑓 0.24 ( 5789 hom., cov: 32)

Exomes 𝑓: 0.31 ( 73939 hom. )

Consequence

CHRNA5
NM_000745.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 7.89

Publications

685 publications found

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]

CHRNA5 links:

ENSG00000261762 (HGNC:):

ENSG00000261762 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_000745.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript

Our verdict: Benign. The variant received -10 points.

BP4

Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Moderate).

BA1

GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.3589 — exceeds 5%% threshold (BA1 applied)

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000745.4. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CHRNA5	NM_000745.4	MANE Select	c.1192G>A	p.Asp398Asn	missense	Exon 5 of 6	NP_000736.2
CHRNA5	NM_001395171.1		c.1115+77G>A		intron	N/A	NP_001382100.1
CHRNA5	NM_001395172.1		c.591+601G>A		intron	N/A	NP_001382101.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CHRNA5	ENST00000299565.9	TSL:1 MANE Select	c.1192G>A	p.Asp398Asn	missense	Exon 5 of 6	ENSP00000299565.5	P30532
CHRNA5	ENST00000913028.1		c.591+601G>A		intron	N/A	ENSP00000583087.1
CHRNA5	ENST00000394802.4	TSL:3	c.521+485G>A		intron	N/A	ENSP00000378281.4	H7BYM0

Frequencies

GnomAD3 genomes

AF:

0.240

AC:

36562

AN:

152040

Hom.:

5789

Cov.:

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.:

AF XY:

0.308

AC XY:

223838

AN XY:

727150

show subpopulations

African (AFR)

AF:

0.0522

AC:

1748

AN:

33476

American (AMR)

AF:

0.171

AC:

7663

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.375

AC:

9800

AN:

26134

East Asian (EAS)

AF:

0.0261

AC:

1035

AN:

39698

South Asian (SAS)

AF:

0.239

AC:

20570

AN:

86246

European-Finnish (FIN)

AF:

0.330

AC:

17593

AN:

53386

Middle Eastern (MID)

AF:

0.372

AC:

2146

AN:

5768

European-Non Finnish (NFE)

AF:

0.335

AC:

372071

AN:

1111828

Other (OTH)

AF:

0.290

AC:

17536

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

16542

33084

49625

66167

82709

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

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.:

AF XY:

0.238

AC XY:

17675

AN XY:

74388

show subpopulations

African (AFR)

AF:

0.0592

AC:

2458

AN:

41526

American (AMR)

AF:

0.226

AC:

3458

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.375

AC:

1302

AN:

3470

East Asian (EAS)

AF:

0.0320

AC:

166

AN:

5186

South Asian (SAS)

AF:

0.222

AC:

1069

AN:

4826

European-Finnish (FIN)

AF:

0.327

AC:

3455

AN:

10568

Middle Eastern (MID)

AF:

0.401

AC:

118

AN:

294

European-Non Finnish (NFE)

AF:

0.347

AC:

23587

AN:

67982

Other (OTH)

AF:

0.275

AC:

581

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1317

2633

3950

5266

6583

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

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

Asia WGS

AF:

0.114

AC:

401

AN:

3478

Local populations

ToMMo 61KJPN (+60KJPN MNV)

AF:

0.0218

AC:

2677

AN:

122722

Turkish Variome

AF:

0.366

AC:

2458

AN:

6716

Hom.:

470

WBBC (Westlake BioBank for Chinese) pilot

AF:

0.0286

AC:

256

AN:

8960

Hom.:

ABraOM SABE-WGS-1171

AF:

0.275

AC:

645

AN:

2342

Hom.:

116

ClinVar

ClinVar submissions

Significance:drug response

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

Susceptibility to severe coronavirus disease (COVID-19) due to high levels of fibrinogen and C-reactive protein (1)

Chronic obstructive pulmonary disease (1)

Lung cancer susceptibility 2 (1)

nicotine response - Toxicity (1)

SMOKING AS A QUANTITATIVE TRAIT LOCUS 3 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.41

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.24

Eigen

Benign

-0.46

Eigen_PC

Benign

-0.43

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.79

MetaRNN

Benign

0.0012

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.3

PhyloP100

7.9

PrimateAI

Benign

0.38

PROVEAN

Benign

-1.4

REVEL

Benign

0.16

Sift

Benign

0.16

Sift4G

Benign

0.070

PromoterAI

-0.022

Neutral

(source)

Varity_R

0.041

gMVP

0.49

Mutation Taster

=74/26

polymorphism (auto)

(source)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

Local populations

ClinVar

Computational scores

Splicing

Publications

Other links and lift over