Genetic Variant CHRNA5:c.413+322G>A (chr15-78588745-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_000745.4(CHRNA5):c.413+322G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0318 in 152,194 control chromosomes in the GnomAD database, including 111 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)

Consequence

CHRNA5
NM_000745.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0820

Publications

7 publications found

Variant links:

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]

CHRNA5 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0318 (4844/152194) while in subpopulation NFE AF = 0.0504 (3426/68024). AF 95% confidence interval is 0.049. There are 111 homozygotes in GnomAd4. There are 2261 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 111 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000745.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
CHRNA5	NM_000745.4	MANE Select	c.413+322G>A	intron	N/A	NP_000736.2
CHRNA5	NM_001395171.1		c.413+322G>A	intron	N/A	NP_001382100.1
CHRNA5	NM_001395172.1		c.413+322G>A	intron	N/A	NP_001382101.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CHRNA5	ENST00000299565.9	TSL:1 MANE Select	c.413+322G>A	intron	N/A	ENSP00000299565.5	P30532
CHRNA5	ENST00000913028.1		c.413+322G>A	intron	N/A	ENSP00000583087.1
CHRNA5	ENST00000394802.4	TSL:3	c.227+322G>A	intron	N/A	ENSP00000378281.4	H7BYM0

Frequencies

GnomAD3 genomes

AF:

0.0319

AC:

4844

AN:

152076

Hom.:

111

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0118

Gnomad AMI

AF:

0.00987

Gnomad AMR

AF:

0.0241

Gnomad ASJ

AF:

0.0179

Gnomad EAS

AF:

0.00866

Gnomad SAS

AF:

0.0199

Gnomad FIN

AF:

0.0263

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.0503

Gnomad OTH

AF:

0.0307

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.0318

AC:

4844

AN:

152194

Hom.:

111

Cov.:

AF XY:

0.0304

AC XY:

2261

AN XY:

74398

show subpopulations

African (AFR)

AF:

0.0118

AC:

491

AN:

41528

American (AMR)

AF:

0.0240

AC:

367

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.0179

AC:

AN:

3468

East Asian (EAS)

AF:

0.00868

AC:

AN:

5182

South Asian (SAS)

AF:

0.0199

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.0263

AC:

279

AN:

10590

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0504

AC:

3426

AN:

68024

Other (OTH)

AF:

0.0299

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

241

483

724

966

1207

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

180

240

300

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0452

Hom.:

228

Bravo

AF:

0.0309

Asia WGS

AF:

0.0170

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

3.1

(source)

DANN

Benign

0.65

PhyloP100

0.082

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over