rs16969968

Positions:

chr15-78590583-G-A

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. 12/20 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

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]

CHRNA5 links:

(HGNC:):

links:

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	Protein	UniProt
CHRNA5	NM_000745.4 linkuse as main transcript	c.1192G>A	p.Asp398Asn	missense_variant	5/6	ENST00000299565.9	NP_000736.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHRNA5	ENST00000299565.9 linkuse as main transcript	c.1192G>A	p.Asp398Asn	missense_variant	5/6	1	NM_000745.4	ENSP00000299565	P1
	ENST00000567141.1 linkuse as main transcript	n.694C>T		non_coding_transcript_exon_variant	1/1

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

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.:

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.:

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 provided

research

HLA Laboratory, Instituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas

- -

Lung cancer susceptibility 2

Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Jul 27, 2010

- -

nicotine response - Toxicity

Other:1

drug response, reviewed by expert panel

curation

PharmGKB

Mar 24, 2021

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

risk factor, no assertion criteria provided

literature only

OMIM

Jul 27, 2010

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.41

CADD

Benign

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

MutationTaster

Benign

0.00015

P;P

PrimateAI

Benign

0.38

PROVEAN

Benign

-1.4

REVEL

Benign

0.16

Sift

Benign

0.16

Sift4G

Benign

0.070

Polyphen

0.045

Vest4

0.071

MPC

0.21

ClinPred

0.060

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over