rs1057910

Variant names:

• chr10-94981296-A-C
• rs1057910
• NM_000771.4:c.1075A>C

Your query was ambiguous. Multiple possible variants found:

• chr10-94981296-A-C
• chr10-94981296-A-G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000771.4(CYP2C9):​c.1075A>C​(p.Ile359Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0634 in 1,613,890 control chromosomes in the GnomAD database, including 3,705 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as drug response,other (★★).

• Frequency:
  • Genomes: 𝑓 0.049 (244 hom., cov: 32)
  • Exomes 𝑓: 0.065 (3461 hom.)
• Consequence: CYP2C9 NM_000771.4 missense
• Clinical Significance: drug response; other criteria provided, multiple submitters, no conflicts O:11
• Conservation: PhyloP100: 0.278
• Publications: 1035 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0023085773).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.106 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP2C9	NM_000771.4	MANE Select	c.1075A>C	p.Ile359Leu	missense	Exon 7 of 9	NP_000762.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP2C9	ENST00000260682.8	TSL:1 MANE Select	c.1075A>C	p.Ile359Leu	missense	Exon 7 of 9	ENSP00000260682.6
	CYP2C9	ENST00000880948.1		c.1096A>C	p.Ile366Leu	missense	Exon 7 of 9	ENSP00000551007.1
	CYP2C9	ENST00000880956.1		c.1096A>C	p.Ile366Leu	missense	Exon 7 of 9	ENSP00000551015.1

Frequencies

GnomAD3 genomes AF: 0.0495 AC: 7523 AN: 152122 Hom.: 245 Cov.: 32

Gnomad AFR AF: 0.0126

Gnomad AMI AF: 0.0296

Gnomad AMR AF: 0.0491

Gnomad ASJ AF: 0.0827

Gnomad EAS AF: 0.0307

Gnomad SAS AF: 0.114

Gnomad FIN AF: 0.0558

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0662

Gnomad OTH AF: 0.0526

GnomAD2 exomes AF: 0.0631 AC: 15849 AN: 251154 AF XY: 0.0682

Gnomad AFR exome AF: 0.0123

Gnomad AMR exome AF: 0.0381

Gnomad ASJ exome AF: 0.0841

Gnomad EAS exome AF: 0.0337

Gnomad FIN exome AF: 0.0626

Gnomad NFE exome AF: 0.0685

Gnomad OTH exome AF: 0.0630

GnomAD4 exome AF: 0.0649 AC: 94818 AN: 1461650 Hom.: 3461 Cov.: 32 AF XY: 0.0662 AC XY: 48127 AN XY: 727130

African (AFR) AF: 0.0127 AC: 425 AN: 33468

American (AMR) AF: 0.0396 AC: 1767 AN: 44666

Ashkenazi Jewish (ASJ) AF: 0.0833 AC: 2176 AN: 26124

East Asian (EAS) AF: 0.0301 AC: 1196 AN: 39698

South Asian (SAS) AF: 0.110 AC: 9478 AN: 86258

European-Finnish (FIN) AF: 0.0627 AC: 3349 AN: 53412

Middle Eastern (MID) AF: 0.0732 AC: 422 AN: 5764

European-Non Finnish (NFE) AF: 0.0649 AC: 72123 AN: 1111880

Other (OTH) AF: 0.0643 AC: 3882 AN: 60380

GnomAD4 genome AF: 0.0494 AC: 7516 AN: 152240 Hom.: 244 Cov.: 32 AF XY: 0.0499 AC XY: 3715 AN XY: 74432

African (AFR) AF: 0.0125 AC: 521 AN: 41556

American (AMR) AF: 0.0490 AC: 749 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0827 AC: 287 AN: 3472

East Asian (EAS) AF: 0.0307 AC: 159 AN: 5172

South Asian (SAS) AF: 0.114 AC: 551 AN: 4828

European-Finnish (FIN) AF: 0.0558 AC: 592 AN: 10608

Middle Eastern (MID) AF: 0.0646 AC: 19 AN: 294

European-Non Finnish (NFE) AF: 0.0662 AC: 4503 AN: 68004

Other (OTH) AF: 0.0511 AC: 108 AN: 2112

Alfa AF: 0.0613 Hom.: 1022

Bravo AF: 0.0462

TwinsUK AF: 0.0612 AC: 227

ALSPAC AF: 0.0633 AC: 244

ESP6500AA AF: 0.0143 AC: 63

ESP6500EA AF: 0.0659 AC: 567

ExAC AF: 0.0636 AC: 7727

Asia WGS AF: 0.0770 AC: 268 AN: 3478

EpiCase AF: 0.0713

EpiControl AF: 0.0737

ClinVar

ClinVar submissions as Germline

Significance: drug response; other

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	-	Flurbiprofen response (1)
-	-	-	Glipizide response (1)
-	-	-	Lesinurad response (1)
-	-	-	not provided (1)
-	-	-	Phenytoin response (2)
-	-	-	Piroxicam response (1)
-	-	-	Tolbutamide response (1)
-	-	-	Warfarin response (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	17
DANN	Benign	0.96
DEOGEN2	Benign	0.096	T
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.090	N
LIST_S2	Benign	0.41	T
MetaRNN	Benign	0.0023	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.8	L
PhyloP100		0.28
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.070
Sift	Uncertain	0.013	D
Sift4G	Benign	0.36	T
Polyphen		0.0020	B
Vest4		0.085
MPC		0.019
ClinPred		0.011	T
GERP RS		1.1
Varity_R		0.64
gMVP		0.039
Mutation Taster		=87/13	polymorphism (auto)

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: rs1057910; hg19: chr10-96741053; COSMIC: COSV53247682;