NM_000770.3:c.416G>A

Variant names:

• chr10-95067273-C-T
• rs11572080
• NM_000770.3:c.416G>A
• CYP2C8 p.Arg139Lys

GermlineCancer (beta)

Variant summary

Our verdict is Likely benign.

-5 Likely Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -5 classification points (ACGS-UK Somatic Oncogenicity v2025). B1_StrongB3_Supporting

The NM_000770.3(CYP2C8):c.416G>A (p.Arg139Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The gene CYP2C8 is a known oncogene (CancerMine: 1 oncogene citations). The variant allele was found at a cumulative frequency of 0.103 (AC=166,794) in the gnomAD database across 1,614,040 control chromosomes, including 9,726 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.118. In-silico predictor (REVEL) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (no review stars). The variant has been observed in cBioPortal in 3 samples across 2 studies and 2 cancer types; somatic enrichment level: SUPPORTING_LOW (Observed in a small number of cBioPortal cases.). This exact variant is curated in the UniProt human variants database as Uncertain Significance; it is also listed as a COSMIC curated somatic variant.

• Frequency:
  • Genomes: 𝑓 0.080 (613 hom., cov: 32)
  • Exomes 𝑓: 0.11 (9113 hom.)
• Consequence: CYP2C8 NM_000770.3 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.144
• Publications: 91 publications found

Genes affected

CYP2C8 (HGNC:2622): (cytochrome P450 family 2 subfamily C member 8) 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 phenobarbital. The enzyme is known to metabolize many xenobiotics, including the anticonvulsive drug mephenytoin, benzo(a)pyrene, 7-ethyoxycoumarin, and the anti-cancer drug taxol. This gene is located within a cluster of cytochrome P450 genes on chromosome 10q24. Several transcript variants encoding a few different isoforms have been found for this gene. [provided by RefSeq, Nov 2010]

Classification according to ACGS-UK Somatic Oncogenicity v2025

Classification was made for transcript:

Our verdict: Likely_benign. The variant received -5 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	B1High frequency in general population		GnomAD effective popmax AF >1% — B1 stand-alone benign; GnomAD effective popmax AF = 0.118 — exceeds 1% threshold (B1 applied)
	B3Computational evidence does not support deleterious effect		Computational evidence does not support a deleterious effect; Missense variant — primary computational scorer does not support an oncogenic/deleterious effect; supports B3

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000770.3. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	CYP2C8 NM_000770.3	MANE Select	c.416G>A p.Arg139Lys	missense	Exon 3 of 9	Prot: NP_000761.3 UniProt:
	CYP2C8 NM_001198853.1		c.206G>A p.Arg69Lys	missense	Exon 3 of 9	Prot: NP_001185782.1 UniProt:
	CYP2C8 NM_001198855.1		c.206G>A p.Arg69Lys	missense	Exon 4 of 10	Prot: NP_001185784.1 UniProt:

CYP2C8 NM_000770.3

MANE Select

HGVSc / HGVSpc.416G>Ap.Arg139Lys

Exon rankExon 3 of 9

missense

Prot: NP_000761.3UniProt: P10632-1

CYP2C8 NM_001198853.1

HGVSc / HGVSpc.206G>Ap.Arg69Lys

Exon rankExon 3 of 9

missense

Prot: NP_001185782.1UniProt: B7Z1F5A0A096LNM3P10632

CYP2C8 NM_001198855.1

HGVSc / HGVSpc.206G>Ap.Arg69Lys

Exon rankExon 4 of 10

missense

Prot: NP_001185784.1UniProt: A0A096LNM3B7Z1F5P10632

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	CYP2C8 ENST00000371270.6	TSL:1MANE Select	c.416G>A p.Arg139Lys	missense	Exon 3 of 9	Prot: ENSP00000360317.3 UniProt:
	CYP2C8 ENST00000854622.1		c.416G>A p.Arg139Lys	missense	Exon 3 of 10	Prot: ENSP00000524681.1 UniProt:
	CYP2C8 ENST00000854631.1		c.416G>A p.Arg139Lys	missense	Exon 3 of 10	Prot: ENSP00000524690.1 UniProt:

CYP2C8 ENST00000371270.6

TSL:1MANE Select

HGVSc / HGVSpc.416G>Ap.Arg139Lys

Exon rankExon 3 of 9

missense

Prot: ENSP00000360317.3UniProt: P10632-1

CYP2C8 ENST00000854622.1

HGVSc / HGVSpc.416G>Ap.Arg139Lys

Exon rankExon 3 of 10

missense

Prot: ENSP00000524681.1UniProt: A0ACI8RQI5

CYP2C8 ENST00000854631.1

HGVSc / HGVSpc.416G>Ap.Arg139Lys

Exon rankExon 3 of 10

missense

Prot: ENSP00000524690.1UniProt: A0ACI8PU51

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.0798	AC:12146	Hom:613	AN:152124	Cov:32
GnomAD2 exomes	AF: 0.0834	AC:20965	Hom:	AN:251460	Cov:
GnomAD4 exome	AF: 0.106	AC:154652	Hom:9113	AN:1461798	Cov:33
GnomAD4 genome	AF: 0.0798	AC:12142	Hom:613	AN:152242	Cov:32
TOPMed (Bravo)	AF: 0.0777	AC:20578	Hom:1077	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.0807	AC:15945	Hom:479	AN:197570	Cov:
Local & regional cohorts 11 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.113	AC:265	Hom:19	AN:2342	Cov:
ChinaMAP Phase 1	AF: 0.00118	AC:	Hom:	AN:	Cov:
Denmark Genome	AF: 0.130	AC:39	Hom:	AN:300	Cov:
ESP6500 (Exome Variant Server)	AF: 0.0853	AC:1110	Hom:	AN:13006	Cov:
GenomeAsia100K	AF: 0.0150	AC:54	Hom:	AN:3478	Cov:
Korea4K (4,157 Koreans)	AF: 0.000276	AC:2	Hom:	AN:7234	Cov:
Qatari Genome	AF: 0.165	AC:29	Hom:	AN:176	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.000171	AC:21	Hom:0	AN:122812	Cov:
Turkish Variome	AF: 0.101	AC:675	Hom:42	AN:6690	Cov:
UK10K	AF: 0.121	AC:914	Hom:	AN:7562	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.000446	AC:4	Hom:0	AN:8960	Cov:

Showing 17 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
ASC(Autism)	0.107 *	1187	11104	0.110 *	1933	17616
BipEx(Bipolar disorder (including schizoaffective))	0.111	3143	28420	0.107	3090	28844
Epi25(Epilepsy)	0.0979	4107	41958	0.0983	6572	66884
SCHEMA(Schizophrenia)	0.0763	9464	124062	0.0954	19193	201202

Showing 4 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	CYP2C8-related disorder (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	9.6
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Benign	0.070	T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.056	N
FuncVEP CTI	Benign	0.010
GPN-Star LLR	N/A	-3.6
GPN-Star score	N/A	3.6
LIST_S2	Benign	0.34	T
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-1.0	T
Mutation Taster	N/A	84/16	polymorphism (auto)
MutationAssessor	Benign	1.6	L
PhyloP100	Benign	0.14
popEVE	Benign	-2.5
PrimateAI	Benign	0.36	T
PromoterAI	N/A	0.030	Neutral
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.039
Sift	Benign	0.19	T
Sift4G	Benign	0.42	T
Varity_R	N/A	0.23
VESM-3B	Benign	-5.0

Showing 28 of 28 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs11572080;

hg19: chr10-96827030;

COSMIC: COSV64875934;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar