NM_000770.3:c.416_417delGGinsCT

Variant names:

• chr10-95067272-CC-AG
• NM_000770.3:c.416_417delGGinsCT
• CYP2C8 p.Arg139Thr

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+2 Uncertain · Warm

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 2 classification points (ACMG Germline Pathogenicity v2019). PM2

The NM_000770.3(CYP2C8):c.416_417delGGinsCT (p.Arg139Thr) variant causes a missense change. Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. 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: 0 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 2 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.

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.416_417delGGinsCT p.Arg139Thr	missense	N/A	Prot: NP_000761.3 UniProt:
	CYP2C8 NM_001198853.1		c.206_207delGGinsCT p.Arg69Thr	missense	N/A	Prot: NP_001185782.1 UniProt:
	CYP2C8 NM_001198855.1		c.206_207delGGinsCT p.Arg69Thr	missense	N/A	Prot: NP_001185784.1 UniProt:

CYP2C8 NM_000770.3

MANE Select

HGVSc / HGVSpc.416_417delGGinsCTp.Arg139Thr

Exon rankN/A

missense

Prot: NP_000761.3UniProt: P10632-1

CYP2C8 NM_001198853.1

HGVSc / HGVSpc.206_207delGGinsCTp.Arg69Thr

Exon rankN/A

missense

Prot: NP_001185782.1UniProt: B7Z1F5A0A096LNM3P10632

CYP2C8 NM_001198855.1

HGVSc / HGVSpc.206_207delGGinsCTp.Arg69Thr

Exon rankN/A

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.416_417delGGinsCT p.Arg139Thr	missense	N/A	Prot: ENSP00000360317.3 UniProt:
	CYP2C8 ENST00000854622.1		c.416_417delGGinsCT p.Arg139Thr	missense	N/A	Prot: ENSP00000524681.1 UniProt:
	CYP2C8 ENST00000854631.1		c.416_417delGGinsCT p.Arg139Thr	missense	N/A	Prot: ENSP00000524690.1 UniProt:

CYP2C8 ENST00000371270.6

TSL:1MANE Select

HGVSc / HGVSpc.416_417delGGinsCTp.Arg139Thr

Exon rankN/A

missense

Prot: ENSP00000360317.3UniProt: P10632-1

CYP2C8 ENST00000854622.1

HGVSc / HGVSpc.416_417delGGinsCTp.Arg139Thr

Exon rankN/A

missense

Prot: ENSP00000524681.1UniProt: A0ACI8RQI5

CYP2C8 ENST00000854631.1

HGVSc / HGVSpc.416_417delGGinsCTp.Arg139Thr

Exon rankN/A

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 2 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 2 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
PhyloP100	Benign	0.14

Showing 1 of 1 scores

Splicing Scores

No splicing scores have been computed for this variant.

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

hg19: chr10-96827029;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar