rs79109919

chr15-78590479-T-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000745.4(CHRNA5):c.1088T>A(p.Leu363Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00304 in 1,614,196 control chromosomes in the GnomAD database, including 116 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.016 (54 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (62 hom.)
• Consequence: CHRNA5 NM_000745.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 7.99

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.014962435).
• BP6: Variant 15-78590479-T-A is Benign according to our data. Variant chr15-78590479-T-A is described in ClinVar as [Benign]. Clinvar id is 714661.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0525 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHRNA5	NM_000745.4	c.1088T>A	p.Leu363Gln	missense_variant	5/6	ENST00000299565.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHRNA5	ENST00000299565.9	c.1088T>A	p.Leu363Gln	missense_variant	5/6	1	NM_000745.4	P1
	ENST00000567141.1	n.798A>T		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.0157 AC: 2387 AN: 152192 Hom.: 54 Cov.: 32

Gnomad AFR AF: 0.0543

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00497

Gnomad ASJ AF: 0.00519

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.0105

GnomAD3 exomes AF: 0.00416 AC: 1046 AN: 251252 Hom.: 24 AF XY: 0.00297 AC XY: 403 AN XY: 135778

Gnomad AFR exome AF: 0.0538

Gnomad AMR exome AF: 0.00220

Gnomad ASJ exome AF: 0.00516

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000255

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00171 AC: 2503 AN: 1461886 Hom.: 62 Cov.: 31 AF XY: 0.00151 AC XY: 1096 AN XY: 727242

Gnomad4 AFR exome AF: 0.0564

Gnomad4 AMR exome AF: 0.00266

Gnomad4 ASJ exome AF: 0.00551

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000151

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000908

Gnomad4 OTH exome AF: 0.00368

GnomAD4 genome AF: 0.0157 AC: 2398 AN: 152310 Hom.: 54 Cov.: 32 AF XY: 0.0151 AC XY: 1122 AN XY: 74486

Gnomad4 AFR AF: 0.0544

Gnomad4 AMR AF: 0.00490

Gnomad4 ASJ AF: 0.00519

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000294

Gnomad4 OTH AF: 0.0104

Alfa AF: 0.00262 Hom.: 5

Bravo AF: 0.0175

ESP6500AA AF: 0.0519 AC: 228

ESP6500EA AF: 0.000582 AC: 5

ExAC AF: 0.00520 AC: 631

Asia WGS AF: 0.00491 AC: 17 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.000415

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Uncertain	0.0
Cadd	Uncertain	26
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.81	D
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
MetaRNN	Benign	0.015	T
MetaSVM	Benign	-0.57	T
MutationAssessor	Pathogenic	3.0	M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-3.7	D
REVEL	Pathogenic	0.73
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.99	D
Vest4		0.87
MVP		0.91
MPC		0.82
ClinPred		0.024	T
GERP RS		4.9
Varity_R		0.74
gMVP		0.83

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs79109919; hg19: chr15-78882821;