chr10-94972183-A-T

Position:

• chr10-94972183-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_000771.4(CYP2C9):​c.899A>T​(p.Glu300Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CYP2C9 NM_000771.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.40

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_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.964

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP2C9	NM_000771.4	c.899A>T	p.Glu300Val	missense_variant	6/9	ENST00000260682.8	NP_000762.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP2C9	ENST00000260682.8	c.899A>T	p.Glu300Val	missense_variant	6/9	1	NM_000771.4	ENSP00000260682	P1
CYP2C9	ENST00000643112.1	c.820-9000A>T		intron_variant, NMD_transcript_variant				ENSP00000496202

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 20, 2024

The c.899A>T (p.E300V) alteration is located in exon 6 (coding exon 6) of the CYP2C9 gene. This alteration results from a A to T substitution at nucleotide position 899, causing the glutamic acid (E) at amino acid position 300 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Uncertain	0.051	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.34	T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.014	T
MetaRNN	Pathogenic	0.96	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Pathogenic	3.2	M
MutationTaster	Benign	0.99	D
PrimateAI	Benign	0.43	T
PROVEAN	Pathogenic	-6.4	D
REVEL	Uncertain	0.32
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.028	D
Polyphen		0.99	D
Vest4		0.61
MutPred		0.93		Loss of disorder (P = 0.0349);
MVP		0.51
MPC		0.034
ClinPred		0.99	D
GERP RS		3.0
Varity_R		0.86
gMVP		0.31

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-96731940;