Genetic Variant CHRNA5:p.Val134Ile (chr15-78588410-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_000745.4(CHRNA5):c.400G>A(p.Val134Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0146 in 1,501,350 control chromosomes in the GnomAD database, including 219 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.010 ( 14 hom., cov: 32)

Exomes 𝑓: 0.015 ( 205 hom. )

Consequence

CHRNA5
NM_000745.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 10.0

Publications

24 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:

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=0.01397571).

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0103 (1569/152270) while in subpopulation SAS AF = 0.0183 (88/4818). AF 95% confidence interval is 0.0165. There are 14 homozygotes in GnomAd4. There are 746 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNA5	NM_000745.4 link	c.400G>A	p.Val134Ile	missense_variant	Exon 4 of 6	ENST00000299565.9	NP_000736.2	P30532Q6EWN4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CHRNA5	ENST00000299565.9 link	c.400G>A	p.Val134Ile	missense_variant	Exon 4 of 6	1	NM_000745.4	ENSP00000299565.5	P30532
CHRNA5	ENST00000394802.4 link	c.214G>A	p.Val72Ile	missense_variant	Exon 3 of 5	3		ENSP00000378281.4	H7BYM0
CHRNA5	ENST00000559554.5 link	c.400G>A	p.Val134Ile	missense_variant	Exon 4 of 6	3		ENSP00000453519.1	H0YM98

Frequencies

GnomAD3 genomes

AF:

0.0103

AC:

1563

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00309

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00766

Gnomad ASJ

AF:

0.00259

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0170

Gnomad FIN

AF:

0.00255

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.0173

Gnomad OTH

AF:

0.0110

GnomAD2 exomes

AF:

0.0114

AC:

2450

AN:

214324

AF XY:

0.0127

show subpopulations

Gnomad AFR exome

AF:

0.00326

Gnomad AMR exome

AF:

0.00681

Gnomad ASJ exome

AF:

0.00351

Gnomad EAS exome

AF:

0.0000658

Gnomad FIN exome

AF:

0.00314

Gnomad NFE exome

AF:

0.0160

Gnomad OTH exome

AF:

0.0108

GnomAD4 exome

AF:

0.0151

AC:

20364

AN:

1349080

Hom.:

205

Cov.:

AF XY:

0.0151

AC XY:

10098

AN XY:

669670

show subpopulations

African (AFR)

AF:

0.00344

AC:

103

AN:

29964

American (AMR)

AF:

0.00687

AC:

240

AN:

34930

Ashkenazi Jewish (ASJ)

AF:

0.00360

AC:

AN:

23596

East Asian (EAS)

AF:

0.000107

AC:

AN:

37544

South Asian (SAS)

AF:

0.0180

AC:

1300

AN:

72280

European-Finnish (FIN)

AF:

0.00316

AC:

162

AN:

51228

Middle Eastern (MID)

AF:

0.0122

AC:

AN:

5316

European-Non Finnish (NFE)

AF:

0.0170

AC:

17629

AN:

1038690

Other (OTH)

AF:

0.0140

AC:

776

AN:

55532

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

776

1552

2329

3105

3881

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

658

1316

1974

2632

3290

<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:

0.0103

AC:

1569

AN:

152270

Hom.:

Cov.:

AF XY:

0.0100

AC XY:

746

AN XY:

74446

show subpopulations

African (AFR)

AF:

0.00308

AC:

128

AN:

41570

American (AMR)

AF:

0.00759

AC:

116

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00259

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.0183

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00255

AC:

AN:

10586

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0173

AC:

1177

AN:

68026

Other (OTH)

AF:

0.0109

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

164

245

327

409

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.0136

Hom.:

Bravo

AF:

0.0102

TwinsUK

AF:

0.0183

AC:

ALSPAC

AF:

0.0179

AC:

ESP6500AA

AF:

0.00319

AC:

ESP6500EA

AF:

0.0192

AC:

165

ExAC

AF:

0.0116

AC:

1404

Asia WGS

AF:

0.00491

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.13

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.14

T;.

Eigen

Pathogenic

0.85

Eigen_PC

Pathogenic

0.83

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

D;D

MetaRNN

Benign

0.014

T;T

MetaSVM

Uncertain

0.17

MutationAssessor

Uncertain

2.2

M;.

PhyloP100

PrimateAI

Uncertain

0.66

PROVEAN

Benign

-0.88

N;N

REVEL

Uncertain

0.49

Sift

Pathogenic

0.0

D;D

Sift4G

Uncertain

0.0020

D;D

Polyphen

1.0

D;.

Vest4

0.21

MPC

0.73

ClinPred

0.042

GERP RS

5.1

Varity_R

0.75

gMVP

0.32

Mutation Taster

=62/38

polymorphism

(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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over