NM_000745.4:c.17C>T

Variant names:

• chr15-78565736-C-T
• rs997031085
• NM_000745.4:c.17C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_000745.4(CHRNA5):​c.17C>T​(p.Ser6Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000247 in 1,188,500 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000093 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00027 (0 hom.)
• Consequence: CHRNA5 NM_000745.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.973
• Publications: 0 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]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.13277516).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNA5	NM_000745.4	MANE Select	c.17C>T	p.Ser6Leu	missense	Exon 1 of 6	NP_000736.2
	CHRNA5	NM_001395171.1		c.17C>T	p.Ser6Leu	missense	Exon 1 of 6	NP_001382100.1
	CHRNA5	NM_001395172.1		c.17C>T	p.Ser6Leu	missense	Exon 1 of 6	NP_001382101.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNA5	ENST00000299565.9	TSL:1 MANE Select	c.17C>T	p.Ser6Leu	missense	Exon 1 of 6	ENSP00000299565.5	P30532
	CHRNA5	ENST00000913028.1		c.17C>T	p.Ser6Leu	missense	Exon 1 of 6	ENSP00000583087.1
	CHRNA5	ENST00000559554.5	TSL:3	c.17C>T	p.Ser6Leu	missense	Exon 1 of 6	ENSP00000453519.1	H0YM98

Frequencies

GnomAD3 genomes AF: 0.0000929 AC: 14 AN: 150762 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000969

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000148

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000269 AC: 279 AN: 1037738 Hom.: 0 Cov.: 29 AF XY: 0.000288 AC XY: 141 AN XY: 489428

African (AFR) AF: 0.0000470 AC: 1 AN: 21294

American (AMR) AF: 0.00 AC: 0 AN: 7006

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12340

East Asian (EAS) AF: 0.00 AC: 0 AN: 22804

South Asian (SAS) AF: 0.00 AC: 0 AN: 19152

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 19450

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2848

European-Non Finnish (NFE) AF: 0.000300 AC: 268 AN: 892412

Other (OTH) AF: 0.000247 AC: 10 AN: 40432

GnomAD4 genome AF: 0.0000929 AC: 14 AN: 150762 Hom.: 0 Cov.: 31 AF XY: 0.0000543 AC XY: 4 AN XY: 73612

African (AFR) AF: 0.0000969 AC: 4 AN: 41280

American (AMR) AF: 0.00 AC: 0 AN: 15128

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5110

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9988

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.000148 AC: 10 AN: 67658

Other (OTH) AF: 0.00 AC: 0 AN: 2078

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.000110

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.015	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	16
DANN	Benign	0.97
DEOGEN2	Benign	0.039	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.095	N
LIST_S2	Benign	0.49	T
M_CAP	Pathogenic	0.69	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.97
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-0.64	N
REVEL	Benign	0.17
Sift	Benign	0.19	T
Sift4G	Benign	0.39	T
Polyphen		0.0	B
Vest4		0.18
MVP		0.50
MPC		0.19
ClinPred		0.10	T
GERP RS		0.48
PromoterAI		-0.096	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.078
gMVP		0.25
Mutation Taster		=90/10	polymorphism

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: rs997031085; hg19: chr15-78858078;