NM_000743.5:c.648A>C

Variant names:

• chr15-78601994-T-G
• rs76821682
• NM_000743.5:c.648A>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000743.5(CHRNA3):​c.648A>C​(p.Lys216Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 151,972 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 Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
• Consequence: CHRNA3 NM_000743.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.385
• Publications: 1 publications found

Genes affected

CHRNA3 (HGNC:1957): (cholinergic receptor nicotinic alpha 3 subunit) This locus encodes a member of the nicotinic acetylcholine receptor family of proteins. Members of this family of proteins form pentameric complexes comprised of both alpha and beta subunits. This locus encodes an alpha-type subunit, as it contains characteristic adjacent cysteine residues. The encoded protein is a ligand-gated ion channel that likely plays a role in neurotransmission. Polymorphisms in this gene have been associated with an increased risk of smoking initiation and an increased susceptibility to lung cancer. Alternatively spliced transcript variants have been described. [provided by RefSeq, Nov 2009]

CHRNA3 Gene-Disease associations (from GenCC):

• urinary bladder, atony of

  Inheritance: AR Classification: STRONG Submitted by: Ambry Genetics, G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.773

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000743.5. 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
	CHRNA3	NM_000743.5	MANE Select	c.648A>C	p.Lys216Asn	missense	Exon 5 of 6	NP_000734.2
	CHRNA3	NM_001166694.2		c.648A>C	p.Lys216Asn	missense	Exon 5 of 6	NP_001160166.1
	CHRNA3	NR_046313.2		n.850A>C		non_coding_transcript_exon	Exon 5 of 8

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNA3	ENST00000326828.6	TSL:1 MANE Select	c.648A>C	p.Lys216Asn	missense	Exon 5 of 6	ENSP00000315602.5
	CHRNA3	ENST00000348639.7	TSL:1	c.648A>C	p.Lys216Asn	missense	Exon 5 of 6	ENSP00000267951.4
	CHRNA3	ENST00000558903.1	TSL:4	n.355A>C		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151972 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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151972 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74242

African (AFR) AF: 0.00 AC: 0 AN: 41362

American (AMR) AF: 0.00 AC: 0 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67970

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	SMOKING AS A QUANTITATIVE TRAIT LOCUS 3;C5231389:Urinary bladder, atony of (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Uncertain	0.017	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	15
DANN	Benign	0.97
DEOGEN2	Uncertain	0.77	D
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.98
FATHMM_MKL	Benign	0.24	N
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.040	D
MetaRNN	Pathogenic	0.77	D
MetaSVM	Uncertain	0.55	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		-0.39
PrimateAI	Pathogenic	0.79	T
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.55
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.011	D
Polyphen		1.0	D
Vest4		0.73
MutPred		0.60		Gain of catalytic residue at K216 (P = 0.001)
MVP		0.71
MPC		0.91
ClinPred		0.99	D
GERP RS		-12
Varity_R		0.70
gMVP		0.82

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: rs76821682; hg19: chr15-78894336;