4-40354014-G-A

Variant names:

• chr4-40354014-G-A
• rs56210055
• NM_017581.4:c.934G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_017581.4(CHRNA9):​c.934G>A​(p.Ala312Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00579 in 1,611,654 control chromosomes in the GnomAD database, including 254 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 0.022 (104 hom., cov: 33)
  • Exomes 𝑓: 0.0041 (150 hom.)
• Consequence: CHRNA9 NM_017581.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.60
• Publications: 7 publications found

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]

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.009749055).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0684 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017581.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNA9	NM_017581.4	MANE Select	c.934G>A	p.Ala312Thr	missense	Exon 5 of 5	NP_060051.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNA9	ENST00000310169.3	TSL:1 MANE Select	c.934G>A	p.Ala312Thr	missense	Exon 5 of 5	ENSP00000312663.2
	CHRNA9	ENST00000509518.1	TSL:3	n.385G>A		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes AF: 0.0220 AC: 3349 AN: 152204 Hom.: 104 Cov.: 33

Gnomad AFR AF: 0.0706

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0107

Gnomad ASJ AF: 0.00806

Gnomad EAS AF: 0.00308

Gnomad SAS AF: 0.0211

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.000999

Gnomad OTH AF: 0.0177

GnomAD2 exomes AF: 0.00928 AC: 2306 AN: 248596 AF XY: 0.00820

Gnomad AFR exome AF: 0.0688

Gnomad AMR exome AF: 0.00839

Gnomad ASJ exome AF: 0.00812

Gnomad EAS exome AF: 0.00343

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.00111

Gnomad OTH exome AF: 0.0109

GnomAD4 exome AF: 0.00409 AC: 5969 AN: 1459332 Hom.: 150 Cov.: 31 AF XY: 0.00433 AC XY: 3141 AN XY: 725512

African (AFR) AF: 0.0705 AC: 2353 AN: 33398

American (AMR) AF: 0.00904 AC: 402 AN: 44484

Ashkenazi Jewish (ASJ) AF: 0.00829 AC: 216 AN: 26058

East Asian (EAS) AF: 0.00144 AC: 57 AN: 39636

South Asian (SAS) AF: 0.0187 AC: 1612 AN: 86142

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53370

Middle Eastern (MID) AF: 0.0170 AC: 98 AN: 5758

European-Non Finnish (NFE) AF: 0.000615 AC: 683 AN: 1110212

Other (OTH) AF: 0.00908 AC: 547 AN: 60274

GnomAD4 genome AF: 0.0220 AC: 3357 AN: 152322 Hom.: 104 Cov.: 33 AF XY: 0.0215 AC XY: 1605 AN XY: 74500

African (AFR) AF: 0.0706 AC: 2933 AN: 41562

American (AMR) AF: 0.0107 AC: 164 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00806 AC: 28 AN: 3472

East Asian (EAS) AF: 0.00308 AC: 16 AN: 5188

South Asian (SAS) AF: 0.0212 AC: 102 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.00100 AC: 68 AN: 68026

Other (OTH) AF: 0.0175 AC: 37 AN: 2116

Alfa AF: 0.00736 Hom.: 81

Bravo AF: 0.0241

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.0670 AC: 295

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.0110 AC: 1333

Asia WGS AF: 0.0180 AC: 64 AN: 3478

EpiCase AF: 0.00120

EpiControl AF: 0.00107

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.17
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	T
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.86	D
MetaRNN	Benign	0.0097	T
MetaSVM	Benign	-0.44	T
MutationAssessor	Benign	1.9	L
PhyloP100		9.6
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.61
Sift	Benign	0.052	T
Sift4G	Benign	0.41	T
Polyphen		0.88	P
Vest4		0.29
MPC		0.35
ClinPred		0.039	T
GERP RS		5.7
Varity_R		0.45
gMVP		0.71
Mutation Taster		=9/91	polymorphism (auto)

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

Other links and lift over

dbSNP: rs56210055; hg19: chr4-40356031;