Genetic Variant NM_017581.4:c.1325A>G (chr4-40354405-A-G) – 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.1325A>G(p.Asn442Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.799 in 1,613,802 control chromosomes in the GnomAD database, including 516,590 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.76 ( 44188 hom., cov: 32)

Exomes 𝑓: 0.80 ( 472402 hom. )

Consequence

CHRNA9
NM_017581.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.33

Publications

34 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=7.2432806E-7).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.845 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNA9	NM_017581.4 link	c.1325A>G	p.Asn442Ser	missense_variant	Exon 5 of 5	ENST00000310169.3	NP_060051.2	Q9UGM1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRNA9	ENST00000310169.3 link	c.1325A>G	p.Asn442Ser	missense_variant	Exon 5 of 5	1	NM_017581.4	ENSP00000312663.2		Q9UGM1

Frequencies

GnomAD3 genomes

AF:

0.760

AC:

115460

AN:

151992

Hom.:

44169

Cov.:

show subpopulations

Gnomad AFR

AF:

0.667

Gnomad AMI

AF:

0.747

Gnomad AMR

AF:

0.688

Gnomad ASJ

AF:

0.789

Gnomad EAS

AF:

0.865

Gnomad SAS

AF:

0.799

Gnomad FIN

AF:

0.797

Gnomad MID

AF:

0.745

Gnomad NFE

AF:

0.814

Gnomad OTH

AF:

0.771

GnomAD2 exomes

AF:

0.780

AC:

196042

AN:

251324

AF XY:

0.787

show subpopulations

Gnomad AFR exome

AF:

0.670

Gnomad AMR exome

AF:

0.646

Gnomad ASJ exome

AF:

0.791

Gnomad EAS exome

AF:

0.867

Gnomad FIN exome

AF:

0.795

Gnomad NFE exome

AF:

0.814

Gnomad OTH exome

AF:

0.787

GnomAD4 exome

AF:

0.803

AC:

1173441

AN:

1461692

Hom.:

472402

Cov.:

AF XY:

0.804

AC XY:

584392

AN XY:

727158

show subpopulations

African (AFR)

AF:

0.662

AC:

22156

AN:

33480

American (AMR)

AF:

0.653

AC:

29221

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.796

AC:

20800

AN:

26136

East Asian (EAS)

AF:

0.838

AC:

33278

AN:

39696

South Asian (SAS)

AF:

0.793

AC:

68375

AN:

86250

European-Finnish (FIN)

AF:

0.792

AC:

42318

AN:

53420

Middle Eastern (MID)

AF:

0.771

AC:

4446

AN:

5768

European-Non Finnish (NFE)

AF:

0.814

AC:

904731

AN:

1111832

Other (OTH)

AF:

0.797

AC:

48116

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

12544

25087

37631

50174

62718

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20856

41712

62568

83424

104280

<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:

0.760

AC:

115534

AN:

152110

Hom.:

44188

Cov.:

AF XY:

0.759

AC XY:

56411

AN XY:

74348

show subpopulations

African (AFR)

AF:

0.667

AC:

27656

AN:

41490

American (AMR)

AF:

0.688

AC:

10512

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.789

AC:

2740

AN:

3472

East Asian (EAS)

AF:

0.866

AC:

4496

AN:

5192

South Asian (SAS)

AF:

0.800

AC:

3847

AN:

4810

European-Finnish (FIN)

AF:

0.797

AC:

8431

AN:

10574

Middle Eastern (MID)

AF:

0.740

AC:

216

AN:

292

European-Non Finnish (NFE)

AF:

0.814

AC:

55324

AN:

67988

Other (OTH)

AF:

0.773

AC:

1632

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1403

2806

4209

5612

7015

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

858

1716

2574

3432

4290

<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:

0.800

Hom.:

231397

Bravo

AF:

0.750

TwinsUK

AF:

0.807

AC:

2992

ALSPAC

AF:

0.812

AC:

3130

ESP6500AA

AF:

0.671

AC:

2958

ESP6500EA

AF:

0.812

AC:

6984

ExAC

AF:

0.784

AC:

95135

Asia WGS

AF:

0.840

AC:

2923

AN:

3478

EpiCase

AF:

0.809

EpiControl

AF:

0.803

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.52

CADD

Benign

8.5

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.11

Eigen

Benign

-0.78

Eigen_PC

Benign

-0.65

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.69

MetaRNN

Benign

7.2e-7

MetaSVM

Benign

-0.96

MutationAssessor

Benign

0.88

PhyloP100

1.3

PrimateAI

Benign

0.28

PROVEAN

Benign

0.16

REVEL

Benign

0.17

Sift

Benign

0.48

Sift4G

Benign

0.76

Polyphen

0.0

Vest4

0.019

MPC

0.054

ClinPred

0.0045

GERP RS

3.1

Varity_R

0.041

gMVP

0.15

Mutation Taster

=98/2

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