rs2256871

Positions:

• chr10-94949217-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000260682.8(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 (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.022 (130 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (118 hom.)
• Consequence: CYP2C9 ENST00000260682.8 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 5.01

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

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP2C9	NM_000771.4	c.752A>G	p.His251Arg	missense_variant	5/9	ENST00000260682.8	NP_000762.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP2C9	ENST00000260682.8	c.752A>G	p.His251Arg	missense_variant	5/9	1	NM_000771.4	ENSP00000260682	P1
CYP2C9	ENST00000473496.1	n.523A>G		non_coding_transcript_exon_variant	4/4	2
CYP2C9	ENST00000643112.1	c.752A>G	p.His251Arg	missense_variant, NMD_transcript_variant	5/8			ENSP00000496202

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

GnomAD3 exomes AF: 0.00532 AC: 1314 AN: 246772 Hom.: 40 AF XY: 0.00383 AC XY: 510 AN XY: 133176

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 SAS exome AF: 0.000138

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

Gnomad4 AFR exome AF: 0.0749

Gnomad4 AMR exome AF: 0.00326

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000254

Gnomad4 SAS exome AF: 0.000379

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000811

Gnomad4 OTH exome AF: 0.00534

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

Gnomad4 AFR AF: 0.0752

Gnomad4 AMR AF: 0.00674

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.0132

Alfa AF: 0.00663 Hom.: 40

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

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 24, 2018	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 10, 2020	- -

Computational scores

Source: dbNSFP v4.3

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
MutationTaster	Benign	0.91	D
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs2256871; hg19: chr10-96708974;