4-40354405-A-G

Position:

• chr4-40354405-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000310169.3(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. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.76 (44188 hom., cov: 32)
  • Exomes 𝑓: 0.80 (472402 hom.)
• Consequence: CHRNA9 ENST00000310169.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.33

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

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt
CHRNA9	NM_017581.4	c.1325A>G	p.Asn442Ser	missense_variant	5/5	ENST00000310169.3	NP_060051.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHRNA9	ENST00000310169.3	c.1325A>G	p.Asn442Ser	missense_variant	5/5	1	NM_017581.4	ENSP00000312663	P1

Frequencies

GnomAD3 genomes AF: 0.760 AC: 115460 AN: 151992 Hom.: 44169 Cov.: 32

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

GnomAD3 exomes AF: 0.780 AC: 196042 AN: 251324 Hom.: 77239 AF XY: 0.787 AC XY: 106836 AN XY: 135836

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 SAS exome AF: 0.796

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.: 50 AF XY: 0.804 AC XY: 584392 AN XY: 727158

Gnomad4 AFR exome AF: 0.662

Gnomad4 AMR exome AF: 0.653

Gnomad4 ASJ exome AF: 0.796

Gnomad4 EAS exome AF: 0.838

Gnomad4 SAS exome AF: 0.793

Gnomad4 FIN exome AF: 0.792

Gnomad4 NFE exome AF: 0.814

Gnomad4 OTH exome AF: 0.797

GnomAD4 genome AF: 0.760 AC: 115534 AN: 152110 Hom.: 44188 Cov.: 32 AF XY: 0.759 AC XY: 56411 AN XY: 74348

Gnomad4 AFR AF: 0.667

Gnomad4 AMR AF: 0.688

Gnomad4 ASJ AF: 0.789

Gnomad4 EAS AF: 0.866

Gnomad4 SAS AF: 0.800

Gnomad4 FIN AF: 0.797

Gnomad4 NFE AF: 0.814

Gnomad4 OTH AF: 0.773

Alfa AF: 0.805 Hom.: 116197

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	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	8.5
DANN	Benign	0.90
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.69	T
MetaRNN	Benign	7.2e-7	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.88	L
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.16	N
REVEL	Benign	0.17
Sift	Benign	0.48	T
Sift4G	Benign	0.76	T
Polyphen		0.0	B
Vest4		0.019
MPC		0.054
ClinPred		0.0045	T
GERP RS		3.1
Varity_R		0.041
gMVP		0.15

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

LitVar

Other links and lift over

dbSNP: rs10009228; hg19: chr4-40356422;