rs12899226

chr15-78595096-T-G

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	UniProt
CHRNA5	NM_000745.4	c.*1843T>G		3_prime_UTR_variant	6/6	ENST00000299565.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHRNA5	ENST00000299565.9	c.*1843T>G		3_prime_UTR_variant	6/6	1	NM_000745.4	P1
CHRNA3	ENST00000348639.7	c.1390-1905A>C		intron_variant		1
CHRNA3	ENST00000559002.5	n.193+1444A>C		intron_variant, non_coding_transcript_variant		1
CHRNA3	ENST00000559658.5	c.*65-1085A>C		intron_variant, NMD_transcript_variant		2

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0149

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0609

Gnomad4 OTH exome AF: 0.0439

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

Gnomad4 AFR AF: 0.0122

Gnomad4 AMR AF: 0.0240

Gnomad4 ASJ AF: 0.0208

Gnomad4 EAS AF: 0.00870

Gnomad4 SAS AF: 0.0197

Gnomad4 FIN AF: 0.0261

Gnomad4 NFE AF: 0.0504

Gnomad4 OTH AF: 0.0293

Alfa AF: 0.0367 Hom.: 30

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

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

Publications

LitVar

Other links and lift over

dbSNP: rs12899226; hg19: chr15-78887438; COSMIC: COSV55140833; COSMIC: COSV55140833;