chr4-40349191-G-A

Variant names:

• chr4-40349191-G-A
• rs55665751
• NM_017581.4:c.675G>A

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_017581.4(CHRNA9):​c.675G>A​(p.Pro225Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00613 in 1,614,098 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0047 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0063 (42 hom.)
• Consequence: CHRNA9 NM_017581.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -3.94
• Publications: 1 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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 4-40349191-G-A is Benign according to our data. Variant chr4-40349191-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 2654736.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-3.94 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNA9	NM_017581.4	MANE Select	c.675G>A	p.Pro225Pro	synonymous	Exon 4 of 5	NP_060051.2	Q9UGM1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNA9	ENST00000310169.3	TSL:1 MANE Select	c.675G>A	p.Pro225Pro	synonymous	Exon 4 of 5	ENSP00000312663.2	Q9UGM1

Frequencies

GnomAD3 genomes AF: 0.00468 AC: 712 AN: 152102 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00118

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00138

Gnomad ASJ AF: 0.00260

Gnomad EAS AF: 0.000384

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.0156

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00673

Gnomad OTH AF: 0.00336

GnomAD2 exomes AF: 0.00485 AC: 1220 AN: 251420 AF XY: 0.00496

Gnomad AFR exome AF: 0.000984

Gnomad AMR exome AF: 0.00104

Gnomad ASJ exome AF: 0.00466

Gnomad EAS exome AF: 0.000435

Gnomad FIN exome AF: 0.0164

Gnomad NFE exome AF: 0.00640

Gnomad OTH exome AF: 0.00359

GnomAD4 exome AF: 0.00628 AC: 9183 AN: 1461880 Hom.: 42 Cov.: 32 AF XY: 0.00612 AC XY: 4453 AN XY: 727242

African (AFR) AF: 0.00111 AC: 37 AN: 33480

American (AMR) AF: 0.00110 AC: 49 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00432 AC: 113 AN: 26136

East Asian (EAS) AF: 0.000403 AC: 16 AN: 39700

South Asian (SAS) AF: 0.000510 AC: 44 AN: 86258

European-Finnish (FIN) AF: 0.0164 AC: 875 AN: 53420

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.00696 AC: 7734 AN: 1111998

Other (OTH) AF: 0.00518 AC: 313 AN: 60396

GnomAD4 genome AF: 0.00468 AC: 713 AN: 152218 Hom.: 3 Cov.: 32 AF XY: 0.00478 AC XY: 356 AN XY: 74410

African (AFR) AF: 0.00118 AC: 49 AN: 41528

American (AMR) AF: 0.00137 AC: 21 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00260 AC: 9 AN: 3466

East Asian (EAS) AF: 0.000385 AC: 2 AN: 5192

South Asian (SAS) AF: 0.000416 AC: 2 AN: 4812

European-Finnish (FIN) AF: 0.0156 AC: 165 AN: 10596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00673 AC: 458 AN: 68024

Other (OTH) AF: 0.00333 AC: 7 AN: 2104

Alfa AF: 0.00537 Hom.: 3

Bravo AF: 0.00359

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00507

EpiControl AF: 0.00569

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.082
DANN	Benign	0.56
PhyloP100		-3.9
Mutation Taster		=99/1	polymorphism

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: rs55665751; hg19: chr4-40351208;