rs12899226

Variant names:

• chr15-78595096-T-G
• rs12899226
• NM_000745.4:c.*1843T>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000745.4(CHRNA5):​c.*1843T>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.033 in 158,372 control chromosomes in the GnomAD database, including 125 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.032 (111 hom., cov: 32)
  • Exomes 𝑓: 0.058 (14 hom.)
• Consequence: CHRNA5 NM_000745.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.504
• Publications: 8 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]

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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0556 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNA5	NM_000745.4	c.*1843T>G		3_prime_UTR_variant	Exon 6 of 6	ENST00000299565.9	NP_000736.2
CHRNA3	NM_000743.5	c.*1508A>C		downstream_gene_variant		ENST00000326828.6	NP_000734.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRNA5	ENST00000299565.9	c.*1843T>G		3_prime_UTR_variant	Exon 6 of 6	1	NM_000745.4	ENSP00000299565.5
CHRNA3	ENST00000326828.6	c.*1508A>C		downstream_gene_variant		1	NM_000743.5	ENSP00000315602.5

Frequencies

GnomAD3 genomes AF: 0.0320 AC: 4865 AN: 152142 Hom.: 111 Cov.: 32

Gnomad AFR AF: 0.0122

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.0240

Gnomad ASJ AF: 0.0208

Gnomad EAS AF: 0.00868

Gnomad SAS AF: 0.0197

Gnomad FIN AF: 0.0261

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0504

Gnomad OTH AF: 0.0301

GnomAD4 exome AF: 0.0578 AC: 353 AN: 6112 Hom.: 14 Cov.: 4 AF XY: 0.0602 AC XY: 180 AN XY: 2988

African (AFR) AF: 0.00 AC: 0 AN: 94

American (AMR) AF: 0.00 AC: 0 AN: 2

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 44

East Asian (EAS) AF: 0.00 AC: 0 AN: 14

South Asian (SAS) AF: 0.0149 AC: 2 AN: 134

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4

Middle Eastern (MID) AF: 0.100 AC: 1 AN: 10

European-Non Finnish (NFE) AF: 0.0609 AC: 340 AN: 5582

Other (OTH) AF: 0.0439 AC: 10 AN: 228

GnomAD4 genome AF: 0.0320 AC: 4866 AN: 152260 Hom.: 111 Cov.: 32 AF XY: 0.0305 AC XY: 2272 AN XY: 74434

African (AFR) AF: 0.0122 AC: 506 AN: 41548

American (AMR) AF: 0.0240 AC: 367 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0208 AC: 72 AN: 3466

East Asian (EAS) AF: 0.00870 AC: 45 AN: 5174

South Asian (SAS) AF: 0.0197 AC: 95 AN: 4822

European-Finnish (FIN) AF: 0.0261 AC: 277 AN: 10606

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0504 AC: 3427 AN: 68030

Other (OTH) AF: 0.0293 AC: 62 AN: 2114

Alfa AF: 0.0444 Hom.: 239

Bravo AF: 0.0310

Asia WGS AF: 0.0170 AC: 58 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	6.2
DANN	Benign	0.50
PhyloP100		0.50
Mutation Taster		=100/0	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: rs12899226; hg19: chr15-78887438; COSMIC: COSV55140833; COSMIC: COSV55140833;