chr15-78590256-C-T

Variant names:

• chr15-78590256-C-T
• NM_000745.4:c.865C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_000745.4(CHRNA5):​c.865C>T​(p.Leu289Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CHRNA5 NM_000745.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.03
• 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]

ENSG00000261762 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.952

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.865C>T	p.Leu289Phe	missense	Exon 5 of 6	NP_000736.2
	CHRNA5	NM_001395171.1		c.865C>T	p.Leu289Phe	missense	Exon 5 of 6	NP_001382100.1
	CHRNA5	NM_001395172.1		c.591+274C>T		intron	N/A	NP_001382101.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNA5	ENST00000299565.9	TSL:1 MANE Select	c.865C>T	p.Leu289Phe	missense	Exon 5 of 6	ENSP00000299565.5	P30532
	CHRNA5	ENST00000913028.1		c.591+274C>T		intron	N/A	ENSP00000583087.1
	CHRNA5	ENST00000394802.4	TSL:3	c.521+158C>T		intron	N/A	ENSP00000378281.4	H7BYM0

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.71	D
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Uncertain	0.50	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		5.0
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-3.9	D
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.90
MutPred		0.79		Gain of catalytic residue at L289 (P = 0.0085)
MVP		0.92
MPC		0.85
ClinPred		0.99	D
GERP RS		5.1
PromoterAI		0.018	Neutral
Varity_R		0.72
gMVP		0.89

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

hg19: chr15-78882598; COSMIC: COSV55137543; COSMIC: COSV55137543;