NM_000771.4:c.818delA

Variant names:

• chr10-94949281-GA-G
• rs9332131
• NM_000771.4:c.818delA

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP6_Very_Strong BS2

The NM_000771.4(CYP2C9):​c.818delA​(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
• Publications: 100 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.

• BP6: Variant 10-94949281-GA-G is Benign according to our data. Variant chr10-94949281-GA-G is described in ClinVar as Benign/Likely_benign|drug_response|other. ClinVar VariationId is 285601.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 472 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.818delA	p.Lys273ArgfsTer34	frameshift splice_region	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.818delA	p.Lys273ArgfsTer34	frameshift splice_region	Exon 5 of 9	ENSP00000260682.6	P11712-1
	CYP2C9	ENST00000880953.1		c.818delA	p.Lys273ArgfsTer2	frameshift	Exon 5 of 8	ENSP00000551012.1
	CYP2C9	ENST00000880948.1		c.818delA	p.Lys273ArgfsTer34	frameshift splice_region	Exon 5 of 9	ENSP00000551007.1

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

GnomAD2 exomes AF: 0.000757 AC: 189 AN: 249618 AF XY: 0.000541

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 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

African (AFR) AF: 0.0126 AC: 420 AN: 33280

American (AMR) AF: 0.000496 AC: 22 AN: 44392

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26006

East Asian (EAS) AF: 0.00 AC: 0 AN: 39382

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85626

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53314

Middle Eastern (MID) AF: 0.000371 AC: 2 AN: 5396

European-Non Finnish (NFE) AF: 0.0000793 AC: 88 AN: 1109076

Other (OTH) AF: 0.000632 AC: 38 AN: 60140

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

African (AFR) AF: 0.0108 AC: 449 AN: 41564

American (AMR) AF: 0.00105 AC: 16 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68016

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000384 Hom.: 0

Bravo AF: 0.00375

Asia WGS AF: 0.000578 AC: 2 AN: 3474

ClinVar

ClinVar submissions

Significance: Benign/Likely benign; drug response; other

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.2
Mutation Taster		=29/171	disease causing (fs/PTC)

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: rs9332131; hg19: chr10-96709038;