rs2256871

Variant names:

• chr10-94949217-A-G
• rs2256871
• NM_000771.4:c.752A>G

Your query was ambiguous. Multiple possible variants found:

• chr10-94949217-A-G
• chr10-94949217-A-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000771.4(CYP2C9):​c.752A>G​(p.His251Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00396 in 1,608,166 control chromosomes in the GnomAD database, including 248 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (130 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (118 hom.)
• Consequence: CYP2C9 NM_000771.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 5.01
• Publications: 54 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=0.0036561787).
• BP6: Variant 10-94949217-A-G is Benign according to our data. Variant chr10-94949217-A-G is described in ClinVar as Benign. ClinVar VariationId is 773002.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.073 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP2C9	NM_000771.4	MANE Select	c.752A>G	p.His251Arg	missense	Exon 5 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.752A>G	p.His251Arg	missense	Exon 5 of 9	ENSP00000260682.6	P11712-1
	CYP2C9	ENST00000880948.1		c.752A>G	p.His251Arg	missense	Exon 5 of 9	ENSP00000551007.1
	CYP2C9	ENST00000880956.1		c.773A>G	p.His258Arg	missense	Exon 5 of 9	ENSP00000551015.1

Frequencies

GnomAD3 genomes AF: 0.0214 AC: 3254 AN: 152146 Hom.: 127 Cov.: 32

Gnomad AFR AF: 0.0748

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00675

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.0134

GnomAD2 exomes AF: 0.00532 AC: 1314 AN: 246772 AF XY: 0.00383

Gnomad AFR exome AF: 0.0744

Gnomad AMR exome AF: 0.00254

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000552

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000142

Gnomad OTH exome AF: 0.00166

GnomAD4 exome AF: 0.00212 AC: 3090 AN: 1455902 Hom.: 118 Cov.: 30 AF XY: 0.00190 AC XY: 1376 AN XY: 723926

African (AFR) AF: 0.0749 AC: 2485 AN: 33184

American (AMR) AF: 0.00326 AC: 143 AN: 43902

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25984

East Asian (EAS) AF: 0.0000254 AC: 1 AN: 39390

South Asian (SAS) AF: 0.000379 AC: 32 AN: 84408

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53278

Middle Eastern (MID) AF: 0.00315 AC: 18 AN: 5722

European-Non Finnish (NFE) AF: 0.0000811 AC: 90 AN: 1109904

Other (OTH) AF: 0.00534 AC: 321 AN: 60130

GnomAD4 genome AF: 0.0215 AC: 3277 AN: 152264 Hom.: 130 Cov.: 32 AF XY: 0.0203 AC XY: 1508 AN XY: 74458

African (AFR) AF: 0.0752 AC: 3126 AN: 41550

American (AMR) AF: 0.00674 AC: 103 AN: 15278

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

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

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.000250 AC: 17 AN: 68010

Other (OTH) AF: 0.0132 AC: 28 AN: 2114

Alfa AF: 0.00813 Hom.: 122

Bravo AF: 0.0240

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0785 AC: 346

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00670 AC: 813

Asia WGS AF: 0.00693 AC: 24 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.31	T
Eigen	Uncertain	0.29
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.92	D
MetaRNN	Benign	0.0037	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	3.4	M
PhyloP100		5.0
PrimateAI	Benign	0.41	T
PROVEAN	Pathogenic	-7.1	D
REVEL	Benign	0.10
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.031	D
Polyphen		0.93	P
Vest4		0.47
MVP		0.53
MPC		0.052
ClinPred		0.12	T
GERP RS		3.2
Varity_R		0.92
gMVP		0.16
Mutation Taster		=77/23	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2256871; hg19: chr10-96708974;