NM_000770.3:c.416G>T

Variant names:

• chr10-95067273-C-A
• rs11572080
• NM_000770.3:c.416G>T
• CYP2C8 p.Arg139Met

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

0 Uncertain · Cold

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 0 classification points (ACMG Germline Pathogenicity v2019). PM2BP4_Moderate

The NM_000770.3(CYP2C8):c.416G>T (p.Arg139Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. In-silico predictor (REVEL) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.R139K: Benign (ClinVar VariationId 545635, 0 stars)

• Frequency: Genomes: not found (cov: 32)
• Consequence: CYP2C8 NM_000770.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.144
• Publications: 212 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 ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 0 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD+AR) (threshold 0.0001) — PM2 moderate.
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Moderate).

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>T p.Arg139Met	missense	Exon 3 of 9	Prot: NP_000761.3 UniProt:
	CYP2C8 NM_001198853.1		c.206G>T p.Arg69Met	missense	Exon 3 of 9	Prot: NP_001185782.1 UniProt:
	CYP2C8 NM_001198855.1		c.206G>T p.Arg69Met	missense	Exon 4 of 10	Prot: NP_001185784.1 UniProt:

CYP2C8 NM_000770.3

MANE Select

HGVSc / HGVSpc.416G>Tp.Arg139Met

Exon rankExon 3 of 9

missense

Prot: NP_000761.3UniProt: P10632-1

CYP2C8 NM_001198853.1

HGVSc / HGVSpc.206G>Tp.Arg69Met

Exon rankExon 3 of 9

missense

Prot: NP_001185782.1UniProt: B7Z1F5A0A096LNM3P10632

CYP2C8 NM_001198855.1

HGVSc / HGVSpc.206G>Tp.Arg69Met

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>T p.Arg139Met	missense	Exon 3 of 9	Prot: ENSP00000360317.3 UniProt:
	CYP2C8 ENST00000854622.1		c.416G>T p.Arg139Met	missense	Exon 3 of 10	Prot: ENSP00000524681.1 UniProt:
	CYP2C8 ENST00000854631.1		c.416G>T p.Arg139Met	missense	Exon 3 of 10	Prot: ENSP00000524690.1 UniProt:

CYP2C8 ENST00000371270.6

TSL:1MANE Select

HGVSc / HGVSpc.416G>Tp.Arg139Met

Exon rankExon 3 of 9

missense

Prot: ENSP00000360317.3UniProt: P10632-1

CYP2C8 ENST00000854622.1

HGVSc / HGVSpc.416G>Tp.Arg139Met

Exon rankExon 3 of 10

missense

Prot: ENSP00000524681.1UniProt: A0ACI8RQI5

CYP2C8 ENST00000854631.1

HGVSc / HGVSpc.416G>Tp.Arg139Met

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 5 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 exome	AF:	AC:	Hom:	AN:	Cov:33
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32
TOPMed (Bravo)	AF: 0.00000378	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00	AC:0	Hom:479	AN:197570	Cov:

Showing 5 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Uncertain	14
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	21
DANN	Benign	0.92
DEOGEN2	Benign	0.27	T
Eigen	Uncertain	0.31
Eigen_PC	Benign	0.14
FATHMM_MKL	Benign	0.28	N
FuncVEP CTI	Pathogenic	0.89
GPN-Star LLR	N/A	-6.0
GPN-Star score	N/A	6.0
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.0041	T
MetaRNN	Benign	0.40	T
MetaSVM	Benign	-0.93	T
Mutation Taster	N/A	35/65	disease causing
MutationAssessor	Pathogenic	3.9	H
PhyloP100	Benign	0.14
popEVE	Benign	-3.3
PrimateAI	Benign	0.35	T
PromoterAI	N/A	0.0023	Neutral
PROVEAN	Pathogenic	-5.0	D
REVEL	Benign	0.18
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Varity_R	N/A	0.86
VESM-3B	Benign	-10

Showing 29 of 29 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;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar