4-40354024-C-T

Position:

• chr4-40354024-C-T

Variant summary

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

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. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.14 (1429 hom., cov: 33)
  • Exomes 𝑓: 0.14 (13788 hom.)
• Consequence: CHRNA9 NM_017581.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.85

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt
CHRNA9	NM_017581.4	c.944C>T	p.Ala315Val	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.944C>T	p.Ala315Val	missense_variant	5/5	1	NM_017581.4	ENSP00000312663.2
CHRNA9	ENST00000509518.1	n.395C>T		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes AF: 0.137 AC: 20775 AN: 152106 Hom.: 1430 Cov.: 33

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

GnomAD3 exomes AF: 0.133 AC: 33246 AN: 249514 Hom.: 2395 AF XY: 0.134 AC XY: 18046 AN XY: 134918

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 SAS exome AF: 0.136

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.: 34 AF XY: 0.135 AC XY: 98338 AN XY: 726950

Gnomad4 AFR exome AF: 0.147

Gnomad4 AMR exome AF: 0.112

Gnomad4 ASJ exome AF: 0.126

Gnomad4 EAS exome AF: 0.158

Gnomad4 SAS exome AF: 0.139

Gnomad4 FIN exome AF: 0.177

Gnomad4 NFE exome AF: 0.134

Gnomad4 OTH exome AF: 0.135

GnomAD4 genome AF: 0.137 AC: 20779 AN: 152224 Hom.: 1429 Cov.: 33 AF XY: 0.135 AC XY: 10063 AN XY: 74434

Gnomad4 AFR AF: 0.144

Gnomad4 AMR AF: 0.116

Gnomad4 ASJ AF: 0.128

Gnomad4 EAS AF: 0.129

Gnomad4 SAS AF: 0.134

Gnomad4 FIN AF: 0.173

Gnomad4 NFE AF: 0.131

Gnomad4 OTH AF: 0.129

Alfa AF: 0.126 Hom.: 1749

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	T
BayesDel_noAF	Benign	-0.36
CADD	Pathogenic	26
DANN	Benign	0.78
DEOGEN2	Benign	0.23	T
Eigen	Benign	0.097
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.90	D
MetaRNN	Benign	0.0021	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	-0.17	N
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-1.7	N
REVEL	Uncertain	0.39
Sift	Benign	0.63	T
Sift4G	Benign	0.65	T
Polyphen		0.84	P
Vest4		0.074
MPC		0.23
ClinPred		0.021	T
GERP RS		4.9
Varity_R		0.19
gMVP		0.62

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: rs55633891; hg19: chr4-40356041; COSMIC: COSV59573873;