rs28371685

Variant names:

• chr10-94981224-C-T
• rs28371685
• NM_000771.4:c.1003C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000771.4(CYP2C9):​c.1003C>T​(p.Arg335Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00353 in 1,613,852 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign,drug response (★★).

• Frequency:
  • Genomes: 𝑓 0.0070 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0032 (17 hom.)
• Consequence: CYP2C9 NM_000771.4 missense
• Clinical Significance: Benign/Likely benign; drug response criteria provided, multiple submitters, no conflicts B:3 O:3
• Conservation: PhyloP100: 1.19
• Publications: 149 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008629888).
• BP6: Variant 10-94981224-C-T is Benign according to our data. Variant chr10-94981224-C-T is described in ClinVar as Benign/Likely_benign|drug_response. ClinVar VariationId is 370010.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00701 (1067/152210) while in subpopulation AFR AF = 0.0174 (721/41552). AF 95% confidence interval is 0.0163. There are 7 homozygotes in GnomAd4. There are 503 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1067 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.1003C>T	p.Arg335Trp	missense	Exon 7 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.1003C>T	p.Arg335Trp	missense	Exon 7 of 9	ENSP00000260682.6	P11712-1
	CYP2C9	ENST00000880948.1		c.1024C>T	p.Arg342Trp	missense	Exon 7 of 9	ENSP00000551007.1
	CYP2C9	ENST00000880956.1		c.1024C>T	p.Arg342Trp	missense	Exon 7 of 9	ENSP00000551015.1

Frequencies

GnomAD3 genomes AF: 0.00702 AC: 1067 AN: 152092 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.0174

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00426

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00187

Gnomad FIN AF: 0.00642

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00285

Gnomad OTH AF: 0.00430

GnomAD2 exomes AF: 0.00359 AC: 901 AN: 251132 AF XY: 0.00337

Gnomad AFR exome AF: 0.0204

Gnomad AMR exome AF: 0.00197

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00550

Gnomad NFE exome AF: 0.00261

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.00317 AC: 4634 AN: 1461642 Hom.: 17 Cov.: 31 AF XY: 0.00313 AC XY: 2274 AN XY: 727118

African (AFR) AF: 0.0195 AC: 654 AN: 33456

American (AMR) AF: 0.00197 AC: 88 AN: 44672

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26124

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39694

South Asian (SAS) AF: 0.00298 AC: 257 AN: 86256

European-Finnish (FIN) AF: 0.00391 AC: 209 AN: 53420

Middle Eastern (MID) AF: 0.00347 AC: 20 AN: 5766

European-Non Finnish (NFE) AF: 0.00289 AC: 3209 AN: 1111874

Other (OTH) AF: 0.00320 AC: 193 AN: 60380

GnomAD4 genome AF: 0.00701 AC: 1067 AN: 152210 Hom.: 7 Cov.: 32 AF XY: 0.00676 AC XY: 503 AN XY: 74406

African (AFR) AF: 0.0174 AC: 721 AN: 41552

American (AMR) AF: 0.00425 AC: 65 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4808

European-Finnish (FIN) AF: 0.00642 AC: 68 AN: 10596

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00285 AC: 194 AN: 68000

Other (OTH) AF: 0.00425 AC: 9 AN: 2116

Alfa AF: 0.00370 Hom.: 6

Bravo AF: 0.00717

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00441 AC: 17

ESP6500AA AF: 0.0191 AC: 84

ESP6500EA AF: 0.00186 AC: 16

ExAC AF: 0.00378 AC: 459

Asia WGS AF: 0.00433 AC: 15 AN: 3478

EpiCase AF: 0.00344

EpiControl AF: 0.00243

ClinVar

ClinVar submissions

Significance: Benign/Likely benign; drug response

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)
-	-	-	Flurbiprofen response (1)
-	-	-	Lesinurad response (1)
-	-	-	Piroxicam response (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	T
Eigen	Uncertain	0.34
Eigen_PC	Benign	0.11
FATHMM_MKL	Benign	0.32	N
LIST_S2	Uncertain	0.93	D
MetaRNN	Benign	0.0086	T
MetaSVM	Benign	-0.38	T
MutationAssessor	Pathogenic	4.8	H
PhyloP100		1.2
PrimateAI	Benign	0.29	T
PROVEAN	Pathogenic	-7.2	D
REVEL	Benign	0.22
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0070	D
Polyphen		1.0	D
Vest4		0.62
MVP		0.88
MPC		0.047
ClinPred		0.090	T
GERP RS		2.9
Varity_R		0.74
gMVP		0.14
Mutation Taster		=60/40	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs28371685; hg19: chr10-96740981; COSMIC: COSV53248410;