chr10-94989020-C-T

Variant names:

• chr10-94989020-C-T
• rs9332239
• NM_000771.4:c.1465C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_000771.4(CYP2C9):​c.1465C>T​(p.Pro489Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00209 in 1,613,944 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 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 0.0017 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (7 hom.)
• Consequence: CYP2C9 NM_000771.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.40
• Publications: 48 publications found

Genes affected

CYP2C9 (HGNC:2623): (cytochrome P450 family 2 subfamily C member 9) This gene encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. This protein localizes to the endoplasmic reticulum and its expression is induced by rifampin. The enzyme is known to metabolize many xenobiotics, including phenytoin, tolbutamide, ibuprofen and S-warfarin. Studies identifying individuals who are poor metabolizers of phenytoin and tolbutamide suggest that this gene is polymorphic. The gene is located within a cluster of cytochrome P450 genes on chromosome 10q24. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.015488237).
• BS2: High AC in GnomAd4 at 253 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000771.4. 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
	CYP2C9	NM_000771.4	MANE Select	c.1465C>T	p.Pro489Ser	missense	Exon 9 of 9	NP_000762.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP2C9	ENST00000260682.8	TSL:1 MANE Select	c.1465C>T	p.Pro489Ser	missense	Exon 9 of 9	ENSP00000260682.6	P11712-1
	CYP2C9	ENST00000880948.1		c.1486C>T	p.Pro496Ser	missense	Exon 9 of 9	ENSP00000551007.1
	CYP2C9	ENST00000880956.1		c.1486C>T	p.Pro496Ser	missense	Exon 9 of 9	ENSP00000551015.1

Frequencies

GnomAD3 genomes AF: 0.00166 AC: 253 AN: 152200 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00314

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00253

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00174 AC: 437 AN: 251320 AF XY: 0.00163

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.00130

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00176

Gnomad NFE exome AF: 0.00286

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00214 AC: 3127 AN: 1461626 Hom.: 7 Cov.: 32 AF XY: 0.00207 AC XY: 1505 AN XY: 727124

African (AFR) AF: 0.000269 AC: 9 AN: 33448

American (AMR) AF: 0.00136 AC: 61 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.000727 AC: 19 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.000174 AC: 15 AN: 86258

European-Finnish (FIN) AF: 0.00187 AC: 100 AN: 53420

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5762

European-Non Finnish (NFE) AF: 0.00251 AC: 2795 AN: 1111846

Other (OTH) AF: 0.00209 AC: 126 AN: 60378

GnomAD4 genome AF: 0.00166 AC: 253 AN: 152318 Hom.: 2 Cov.: 32 AF XY: 0.00154 AC XY: 115 AN XY: 74472

African (AFR) AF: 0.000337 AC: 14 AN: 41576

American (AMR) AF: 0.00314 AC: 48 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00113 AC: 12 AN: 10616

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

European-Non Finnish (NFE) AF: 0.00253 AC: 172 AN: 68032

Other (OTH) AF: 0.00189 AC: 4 AN: 2112

Alfa AF: 0.00241 Hom.: 4

Bravo AF: 0.00187

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00244 AC: 21

ExAC AF: 0.00191 AC: 232

EpiCase AF: 0.00196

EpiControl AF: 0.00213

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.38	T
Eigen	Benign	0.036
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.53	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.0042	T
MetaRNN	Benign	0.015	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		2.4
PrimateAI	Benign	0.41	T
PROVEAN	Pathogenic	-6.9	D
REVEL	Benign	0.11
Sift	Uncertain	0.0050	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.98	D
Vest4		0.15
MVP		0.56
MPC		0.030
ClinPred		0.10	T
GERP RS		2.5
Varity_R		0.73
gMVP		0.46
Mutation Taster		=85/15	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: rs9332239; hg19: chr10-96748777;