15-78589891-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000745.4(CHRNA5):c.500A>G(p.Lys167Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000896 in 1,614,168 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0050 (6 hom., cov: 32)
  • Exomes 𝑓: 0.00047 (3 hom.)
• Consequence: CHRNA5 NM_000745.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 9.32

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=0.025515765).
• BP6: Variant 15-78589891-A-G is Benign according to our data. Variant chr15-78589891-A-G is described in ClinVar as [Benign]. Clinvar id is 776936.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00499 (760/152310) while in subpopulation AFR AF= 0.0173 (720/41560). AF 95% confidence interval is 0.0163. There are 6 homozygotes in gnomad4. There are 378 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHRNA5	NM_000745.4	c.500A>G	p.Lys167Arg	missense_variant	5/6	ENST00000299565.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHRNA5	ENST00000299565.9	c.500A>G	p.Lys167Arg	missense_variant	5/6	1	NM_000745.4	P1
	ENST00000567141.1	n.1386T>C		non_coding_transcript_exon_variant	1/1
CHRNA5	ENST00000394802.4	c.317A>G	p.Lys106Arg	missense_variant	4/5	3
CHRNA5	ENST00000559554.5	c.458+42A>G		intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.00497 AC: 756 AN: 152192 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.0173

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00209

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00133 AC: 334 AN: 251360 Hom.: 3 AF XY: 0.00102 AC XY: 139 AN XY: 135842

Gnomad AFR exome AF: 0.0178

Gnomad AMR exome AF: 0.000926

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000469 AC: 686 AN: 1461858 Hom.: 3 Cov.: 31 AF XY: 0.000410 AC XY: 298 AN XY: 727220

Gnomad4 AFR exome AF: 0.0167

Gnomad4 AMR exome AF: 0.00105

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000108

Gnomad4 OTH exome AF: 0.000993

GnomAD4 genome AF: 0.00499 AC: 760 AN: 152310 Hom.: 6 Cov.: 32 AF XY: 0.00507 AC XY: 378 AN XY: 74486

Gnomad4 AFR AF: 0.0173

Gnomad4 AMR AF: 0.00209

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000792 Hom.: 1

Bravo AF: 0.00557

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0191 AC: 84

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00158 AC: 192

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.00

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	Benign	0.13
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.11
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.55	D
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D
MetaRNN	Benign	0.026	T
MetaSVM	Uncertain	0.19	D
MutationAssessor	Benign	1.7	L
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-2.9	D
REVEL	Pathogenic	0.72
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.81
MVP		0.92
MPC		0.73
ClinPred		0.036	T
GERP RS		5.4
Varity_R		0.72
gMVP		0.66

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: rs80087508; hg19: chr15-78882233;