Genetic Variant CHRNA9:p.Ala315Val (chr4-40354024-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_017581.4(CHRNA9):c.944C>T(p.Ala315Val) variant causes a missense change. The variant allele was found at a frequency of 0.136 in 1,613,552 control chromosomes in the GnomAD database, including 15,217 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 0.14 ( 1429 hom., cov: 33)

Exomes 𝑓: 0.14 ( 13788 hom. )

Consequence

CHRNA9
NM_017581.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.85

Publications

21 publications found

Variant links:

Genes affected

CHRNA9 (HGNC:14079): (cholinergic receptor nicotinic alpha 9 subunit) This gene is a member of the ligand-gated ionic channel family and nicotinic acetylcholine receptor gene superfamily. It encodes a plasma membrane protein that forms homo- or hetero-oligomeric divalent cation channels. This protein is involved in cochlea hair cell development and is also expressed in the outer hair cells (OHCs) of the adult cochlea. [provided by RefSeq, Feb 2012]

CHRNA9 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.0020789206).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.141 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNA9	NM_017581.4 link	c.944C>T	p.Ala315Val	missense_variant	Exon 5 of 5	ENST00000310169.3	NP_060051.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRNA9	ENST00000310169.3 link	c.944C>T	p.Ala315Val	missense_variant	Exon 5 of 5	1	NM_017581.4	ENSP00000312663.2
CHRNA9	ENST00000509518.1 link	n.395C>T		non_coding_transcript_exon_variant	Exon 2 of 2	3

Frequencies

GnomAD3 genomes

AF:

0.137

AC:

20775

AN:

152106

Hom.:

1430

Cov.:

show subpopulations

Gnomad AFR

AF:

0.144

Gnomad AMI

AF:

0.226

Gnomad AMR

AF:

0.116

Gnomad ASJ

AF:

0.128

Gnomad EAS

AF:

0.130

Gnomad SAS

AF:

0.134

Gnomad FIN

AF:

0.173

Gnomad MID

AF:

0.152

Gnomad NFE

AF:

0.131

Gnomad OTH

AF:

0.130

GnomAD2 exomes

AF:

0.133

AC:

33246

AN:

249514

AF XY:

0.134

show subpopulations

Gnomad AFR exome

AF:

0.142

Gnomad AMR exome

AF:

0.111

Gnomad ASJ exome

AF:

0.130

Gnomad EAS exome

AF:

0.128

Gnomad FIN exome

AF:

0.175

Gnomad NFE exome

AF:

0.131

Gnomad OTH exome

AF:

0.133

GnomAD4 exome

AF:

0.136

AC:

198121

AN:

1461328

Hom.:

13788

Cov.:

AF XY:

0.135

AC XY:

98338

AN XY:

726950

show subpopulations

African (AFR)

AF:

0.147

AC:

4933

AN:

33470

American (AMR)

AF:

0.112

AC:

4986

AN:

44694

Ashkenazi Jewish (ASJ)

AF:

0.126

AC:

3293

AN:

26108

East Asian (EAS)

AF:

0.158

AC:

6282

AN:

39696

South Asian (SAS)

AF:

0.139

AC:

11959

AN:

86214

European-Finnish (FIN)

AF:

0.177

AC:

9433

AN:

53396

Middle Eastern (MID)

AF:

0.111

AC:

639

AN:

5768

European-Non Finnish (NFE)

AF:

0.134

AC:

148449

AN:

1111608

Other (OTH)

AF:

0.135

AC:

8147

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

9195

18390

27584

36779

45974

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5502

11004

16506

22008

27510

<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

AF:

0.137

AC:

20779

AN:

152224

Hom.:

1429

Cov.:

AF XY:

0.135

AC XY:

10063

AN XY:

74434

show subpopulations

African (AFR)

AF:

0.144

AC:

5997

AN:

41544

American (AMR)

AF:

0.116

AC:

1767

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.128

AC:

443

AN:

3470

East Asian (EAS)

AF:

0.129

AC:

670

AN:

5186

South Asian (SAS)

AF:

0.134

AC:

644

AN:

4820

European-Finnish (FIN)

AF:

0.173

AC:

1835

AN:

10598

Middle Eastern (MID)

AF:

0.156

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.131

AC:

8899

AN:

67996

Other (OTH)

AF:

0.129

AC:

273

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

943

1885

2828

3770

4713

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

222

444

666

888

1110

<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:

0.129

Hom.:

3939

Bravo

AF:

0.133

TwinsUK

AF:

0.146

AC:

540

ALSPAC

AF:

0.135

AC:

520

ESP6500AA

AF:

0.143

AC:

630

ESP6500EA

AF:

0.131

AC:

1127

ExAC

AF:

0.135

AC:

16352

Asia WGS

AF:

0.111

AC:

386

AN:

3478

EpiCase

AF:

0.128

EpiControl

AF:

0.133

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.36

CADD

Pathogenic

(source)

DANN

Benign

0.78

DEOGEN2

Benign

0.23

Eigen

Benign

0.097

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.90

MetaRNN

Benign

0.0021

MetaSVM

Benign

-0.90

MutationAssessor

Benign

-0.17

PhyloP100

5.8

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-1.7

REVEL

Uncertain

0.39

Sift

Benign

0.63

Sift4G

Benign

0.65

Polyphen

0.84

Vest4

0.074

MPC

0.23

ClinPred

0.021

GERP RS

4.9

Varity_R

0.19

gMVP

0.62

Mutation Taster

=74/26

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over