15-78565773-G-C

Variant names:

• chr15-78565773-G-C
• rs534031880
• NM_000745.4:c.54G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000745.4(CHRNA5):​c.54G>C​(p.Gln18His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000328 in 1,218,644 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. Q18Q) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: CHRNA5 NM_000745.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.19
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22769618).

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.54G>C	p.Gln18His	missense	Exon 1 of 6	NP_000736.2
	CHRNA5	NM_001395171.1		c.54G>C	p.Gln18His	missense	Exon 1 of 6	NP_001382100.1
	CHRNA5	NM_001395172.1		c.54G>C	p.Gln18His	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.54G>C	p.Gln18His	missense	Exon 1 of 6	ENSP00000299565.5	P30532
	CHRNA5	ENST00000913028.1		c.54G>C	p.Gln18His	missense	Exon 1 of 6	ENSP00000583087.1
	CHRNA5	ENST00000559554.5	TSL:3	c.54G>C	p.Gln18His	missense	Exon 1 of 6	ENSP00000453519.1	H0YM98

Frequencies

GnomAD3 genomes AF: 0.00000662 AC: 1 AN: 151166 Hom.: 0 Cov.: 31

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: 0.0000148

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000281 AC: 3 AN: 1067478 Hom.: 0 Cov.: 30 AF XY: 0.00000198 AC XY: 1 AN XY: 504046

African (AFR) AF: 0.00 AC: 0 AN: 22372

American (AMR) AF: 0.00 AC: 0 AN: 7992

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13722

East Asian (EAS) AF: 0.00 AC: 0 AN: 25724

South Asian (SAS) AF: 0.00 AC: 0 AN: 19400

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 20816

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2894

European-Non Finnish (NFE) AF: 0.00000329 AC: 3 AN: 911872

Other (OTH) AF: 0.00 AC: 0 AN: 42686

GnomAD4 genome AF: 0.00000662 AC: 1 AN: 151166 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 73816

African (AFR) AF: 0.00 AC: 0 AN: 41256

American (AMR) AF: 0.00 AC: 0 AN: 15180

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5120

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10246

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 308

European-Non Finnish (NFE) AF: 0.0000148 AC: 1 AN: 67772

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

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.0085	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	18
DANN	Benign	0.94
DEOGEN2	Benign	0.050	T
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.36	T
M_CAP	Pathogenic	0.75	D
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	0.0	N
PhyloP100		1.2
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	0.23	N
REVEL	Benign	0.19
Sift	Benign	0.54	T
Sift4G	Benign	0.55	T
Polyphen		0.025	B
Vest4		0.18
MutPred		0.44		Loss of disorder (P = 0.0745)
MVP		0.65
MPC		0.20
ClinPred		0.12	T
GERP RS		2.5
PromoterAI		-0.073	Neutral
Varity_R		0.078
gMVP		0.39
Mutation Taster		=88/12	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: rs534031880; hg19: chr15-78858115;