rs2229961

Positions:

• chr15-78588410-G-A
• chr15-78588410-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_000745.4(CHRNA5):​c.400G>A​(p.Val134Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0146 in 1,501,350 control chromosomes in the GnomAD database, including 219 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. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.010 (14 hom., cov: 32)
  • Exomes 𝑓: 0.015 (205 hom.)
• Consequence: CHRNA5 NM_000745.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 10.0

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

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01397571).
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0103 (1569/152270) while in subpopulation SAS AF= 0.0183 (88/4818). AF 95% confidence interval is 0.0165. There are 14 homozygotes in gnomad4. There are 746 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHRNA5	NM_000745.4	c.400G>A	p.Val134Ile	missense_variant	4/6	ENST00000299565.9	NP_000736.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHRNA5	ENST00000299565.9	c.400G>A	p.Val134Ile	missense_variant	4/6	1	NM_000745.4	ENSP00000299565.5
CHRNA5	ENST00000394802.4	c.214G>A	p.Val72Ile	missense_variant	3/5	3		ENSP00000378281.4
CHRNA5	ENST00000559554.5	c.400G>A	p.Val134Ile	missense_variant	4/6	3		ENSP00000453519.1

Frequencies

GnomAD3 genomes AF: 0.0103 AC: 1563 AN: 152150 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.00309

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00766

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0170

Gnomad FIN AF: 0.00255

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.0173

Gnomad OTH AF: 0.0110

GnomAD3 exomes AF: 0.0114 AC: 2450 AN: 214324 Hom.: 28 AF XY: 0.0127 AC XY: 1477 AN XY: 116584

Gnomad AFR exome AF: 0.00326

Gnomad AMR exome AF: 0.00681

Gnomad ASJ exome AF: 0.00351

Gnomad EAS exome AF: 0.0000658

Gnomad SAS exome AF: 0.0187

Gnomad FIN exome AF: 0.00314

Gnomad NFE exome AF: 0.0160

Gnomad OTH exome AF: 0.0108

GnomAD4 exome AF: 0.0151 AC: 20364 AN: 1349080 Hom.: 205 Cov.: 20 AF XY: 0.0151 AC XY: 10098 AN XY: 669670

Gnomad4 AFR exome AF: 0.00344

Gnomad4 AMR exome AF: 0.00687

Gnomad4 ASJ exome AF: 0.00360

Gnomad4 EAS exome AF: 0.000107

Gnomad4 SAS exome AF: 0.0180

Gnomad4 FIN exome AF: 0.00316

Gnomad4 NFE exome AF: 0.0170

Gnomad4 OTH exome AF: 0.0140

GnomAD4 genome AF: 0.0103 AC: 1569 AN: 152270 Hom.: 14 Cov.: 32 AF XY: 0.0100 AC XY: 746 AN XY: 74446

Gnomad4 AFR AF: 0.00308

Gnomad4 AMR AF: 0.00759

Gnomad4 ASJ AF: 0.00259

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0183

Gnomad4 FIN AF: 0.00255

Gnomad4 NFE AF: 0.0173

Gnomad4 OTH AF: 0.0109

Alfa AF: 0.0139 Hom.: 17

Bravo AF: 0.0102

TwinsUK AF: 0.0183 AC: 68

ALSPAC AF: 0.0179 AC: 69

ESP6500AA AF: 0.00319 AC: 14

ESP6500EA AF: 0.0192 AC: 165

ExAC AF: 0.0116 AC: 1404

Asia WGS AF: 0.00491 AC: 17 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.13
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T;.
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D
MetaRNN	Benign	0.014	T;T
MetaSVM	Uncertain	0.17	D
MutationAssessor	Uncertain	2.2	M;.
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.88	N;N
REVEL	Uncertain	0.49
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		1.0	D;.
Vest4		0.21
MPC		0.73
ClinPred		0.042	T
GERP RS		5.1
Varity_R		0.75
gMVP		0.32

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: rs2229961; hg19: chr15-78880752;