Genetic Variant CHRNA5:p.Val134Phe (chr15-78588410-G-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_000745.4(CHRNA5):c.400G>T(p.Val134Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000296 in 1,349,656 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000030 ( 0 hom. )

Consequence

CHRNA5
NM_000745.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 10.0

Publications

24 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: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.91

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNA5	NM_000745.4 link	c.400G>T	p.Val134Phe	missense_variant	Exon 4 of 6	ENST00000299565.9	NP_000736.2	P30532Q6EWN4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CHRNA5	ENST00000299565.9 link	c.400G>T	p.Val134Phe	missense_variant	Exon 4 of 6	1	NM_000745.4	ENSP00000299565.5	P30532
CHRNA5	ENST00000394802.4 link	c.214G>T	p.Val72Phe	missense_variant	Exon 3 of 5	3		ENSP00000378281.4	H7BYM0
CHRNA5	ENST00000559554.5 link	c.400G>T	p.Val134Phe	missense_variant	Exon 4 of 6	3		ENSP00000453519.1	H0YM98

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000933

AC:

AN:

214324

AF XY:

0.00000858

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000194

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000296

AC:

AN:

1349656

Hom.:

Cov.:

AF XY:

0.00000299

AC XY:

AN XY:

669940

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

29970

American (AMR)

AF:

0.00

AC:

AN:

34934

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23598

East Asian (EAS)

AF:

0.00

AC:

AN:

37544

South Asian (SAS)

AF:

0.00

AC:

AN:

72288

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51228

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5318

European-Non Finnish (NFE)

AF:

0.00000385

AC:

AN:

1039236

Other (OTH)

AF:

0.00

AC:

AN:

55540

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.538

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.68

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.38

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.56

D;.

Eigen

Pathogenic

0.94

Eigen_PC

Pathogenic

0.89

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

D;D

M_CAP

Uncertain

0.23

MetaRNN

Pathogenic

0.91

D;D

MetaSVM

Uncertain

0.53

MutationAssessor

Uncertain

2.6

M;.

PhyloP100

PrimateAI

Uncertain

0.77

PROVEAN

Pathogenic

-4.6

D;D

REVEL

Pathogenic

0.80

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0010

D;D

Polyphen

1.0

D;.

Vest4

0.86

MutPred

0.62

Loss of stability (P = 0.1209);Loss of stability (P = 0.1209);

MVP

0.92

MPC

0.94

ClinPred

1.0

GERP RS

5.1

Varity_R

0.98

gMVP

0.83

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over