chr15-78590104-C-T

Variant names:

• chr15-78590104-C-T
• rs61742337
• NM_000745.4:c.713C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PP3_Moderate BP6_Moderate

The NM_000745.4(CHRNA5):​c.713C>T​(p.Pro238Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000115 in 1,614,076 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000099 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: CHRNA5 NM_000745.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter U:1 B:1
• Conservation: PhyloP100: 7.90
• Publications: 13 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: Uncertain_significance. The variant received 0 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.93
• BP6: Variant 15-78590104-C-T is Benign according to our data. Variant chr15-78590104-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1050664.Status of the report is criteria_provided_single_submitter, 1 stars.

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.713C>T	p.Pro238Leu	missense	Exon 5 of 6	NP_000736.2
	CHRNA5	NM_001395171.1		c.713C>T	p.Pro238Leu	missense	Exon 5 of 6	NP_001382100.1
	CHRNA5	NM_001395173.1		c.713C>T	p.Pro238Leu	missense splice_region	Exon 5 of 6	NP_001382102.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNA5	ENST00000299565.9	TSL:1 MANE Select	c.713C>T	p.Pro238Leu	missense	Exon 5 of 6	ENSP00000299565.5	P30532
	CHRNA5	ENST00000913028.1		c.591+122C>T		intron	N/A	ENSP00000583087.1
	CHRNA5	ENST00000394802.4	TSL:3	c.521+6C>T		splice_region intron	N/A	ENSP00000378281.4	H7BYM0

Frequencies

GnomAD3 genomes AF: 0.0000986 AC: 15 AN: 152092 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.000221

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000916 AC: 23 AN: 251168 AF XY: 0.0000958

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000194

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000117 AC: 171 AN: 1461866 Hom.: 0 Cov.: 31 AF XY: 0.000117 AC XY: 85 AN XY: 727236

African (AFR) AF: 0.0000597 AC: 2 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.0000749 AC: 4 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000139 AC: 155 AN: 1111996

Other (OTH) AF: 0.000149 AC: 9 AN: 60396

GnomAD4 genome AF: 0.0000985 AC: 15 AN: 152210 Hom.: 0 Cov.: 32 AF XY: 0.0000940 AC XY: 7 AN XY: 74436

African (AFR) AF: 0.00 AC: 0 AN: 41514

American (AMR) AF: 0.00 AC: 0 AN: 15286

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000221 AC: 15 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000219 Hom.: 0

Bravo AF: 0.000113

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000140 AC: 17

EpiCase AF: 0.0000545

EpiControl AF: 0.000356

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	1	-	SMOKING AS A QUANTITATIVE TRAIT LOCUS 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Pathogenic	0.30
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.58	D
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Uncertain	0.22	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		7.9
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-3.9	D
REVEL	Pathogenic	0.70
Sift	Uncertain	0.015	D
Sift4G	Uncertain	0.018	D
Polyphen		1.0	D
Vest4		0.93
MVP		0.93
MPC		0.82
ClinPred		0.54	D
GERP RS		5.2
PromoterAI		-0.0016	Neutral
Varity_R		0.59
gMVP		0.93
Mutation Taster		=4/96	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs61742337; hg19: chr15-78882446; COSMIC: COSV55139314; COSMIC: COSV55139314;