chr10-94949281-GA-G

Position:

• chr10-94949281-GA-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_000771.4(CYP2C9):​c.818del​(p.Lys273ArgfsTer34) variant causes a frameshift, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000648 in 1,608,842 control chromosomes in the GnomAD database, including 5 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign,drug response,other (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0031 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00039 (2 hom.)
• Consequence: CYP2C9 NM_000771.4 frameshift, splice_region
• Clinical Significance: Benign/Likely benign; drug response; other criteria provided, multiple submitters, no conflicts B:2 O:4
• Conservation: PhyloP100: -1.21

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 Likely_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAd4 at 472 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP2C9	NM_000771.4	c.818del	p.Lys273ArgfsTer34	frameshift_variant, splice_region_variant	5/9	ENST00000260682.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP2C9	ENST00000260682.8	c.818del	p.Lys273ArgfsTer34	frameshift_variant, splice_region_variant	5/9	1	NM_000771.4	P1
CYP2C9	ENST00000473496.1	n.589del		non_coding_transcript_exon_variant	4/4	2
CYP2C9	ENST00000643112.1	c.818del	p.Lys273SerfsTer2	frameshift_variant, splice_region_variant, NMD_transcript_variant	5/8

Frequencies

GnomAD3 genomes AF: 0.00310 AC: 472 AN: 152112 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.0108

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000757 AC: 189 AN: 249618 Hom.: 1 AF XY: 0.000541 AC XY: 73 AN XY: 134944

Gnomad AFR exome AF: 0.0106

Gnomad AMR exome AF: 0.000264

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000884

Gnomad OTH exome AF: 0.00132

GnomAD4 exome AF: 0.000392 AC: 571 AN: 1456612 Hom.: 2 Cov.: 29 AF XY: 0.000342 AC XY: 248 AN XY: 724694

Gnomad4 AFR exome AF: 0.0126

Gnomad4 AMR exome AF: 0.000496

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000793

Gnomad4 OTH exome AF: 0.000632

GnomAD4 genome AF: 0.00310 AC: 472 AN: 152230 Hom.: 3 Cov.: 32 AF XY: 0.00312 AC XY: 232 AN XY: 74410

Gnomad4 AFR AF: 0.0108

Gnomad4 AMR AF: 0.00105

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000384 Hom.: 0

Bravo AF: 0.00375

Asia WGS AF: 0.000578 AC: 2 AN: 3474

ClinVar

Significance: Benign/Likely benign; drug response; other

Submissions summary: Benign:2 Other:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2 Other:1

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 14, 2021	- -
other, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 28, 2015	- Variant classified as "other reportable" ??? variant is clinically benign (not associated with disease) but is reported when observed (e.g. pseudodeficiency alleles).
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 06, 2018	- -

Piroxicam response Other:1

drug response, criteria provided, single submitter

curation

Medical Genetics Summaries

Feb 11, 2019

Individuals with 2 decreased function alleles (CYP2C9 poor metabolizers) have reduced clearance of piroxicam. Because the standard recommended dose of piroxicam may cause abnormally high plasma levels, a dose reduction should be considered for these individuals. Poor metabolizer

Lesinurad response Other:1

drug response, criteria provided, single submitter

curation

Medical Genetics Summaries

Feb 11, 2019

Lesinurad should be used with caution in individuals with 2 decreased function alleles (CYP2C9 poor metabolizers) because of increased exposure and an increased risk of side effects. Poor metabolizer

Flurbiprofen response Other:1

drug response, criteria provided, single submitter

curation

Medical Genetics Summaries

Feb 11, 2019

The dose of flurbiprofen should be reduced in individuals with 2 decreased function alleles (CYP2C9 poor metabolizers) to avoid abnormally high plasma levels due to reduced metabolic clearance. Poor metabolizer

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs9332131; hg19: chr10-96709038;