chr15-78590583-G-A

Variant names:

• chr15-78590583-G-A
• rs16969968
• NM_000745.4:c.1192G>A

Variant summary

Our verdict is Benign. The variant received -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. 13/21 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
• Publications: 676 publications found

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]

ENSG00000261762 (HGNC:):

ACMG classification

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.

Variant Effect in Transcripts

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

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	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

Selected	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
	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

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

GnomAD2 exomes AF: 0.264 AC: 66316 AN: 250966 AF XY: 0.276

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

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

GnomAD4 genome AF: 0.240 AC: 36562 AN: 152158 Hom.: 5789 Cov.: 32 AF XY: 0.238 AC XY: 17675 AN XY: 74388

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

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

ClinVar submissions as Germline

Significance: drug response

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	1	-	Susceptibility to severe coronavirus disease (COVID-19) due to high levels of fibrinogen and C-reactive protein (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	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
PhyloP100		7.9
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
PromoterAI		-0.022	Neutral
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

Other links and lift over

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