rs16969968

chr15-78590583-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

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
• Clinical Significance: drug response reviewed by expert panel U:1 O:3
• Conservation: PhyloP100: 7.89

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]

(HGNC:):

ACMG classification

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
CHRNA5	NM_000745.4	c.1192G>A	p.Asp398Asn	missense_variant	5/6	ENST00000299565.9

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.240 AC: 36562 AN: 152040 Hom.: 5789 Cov.: 32

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

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

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

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:1 Other:3

Revision: reviewed by expert panel

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	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

Other links and lift over

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