10-94942234-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_000771.4(CYP2C9):c.374G>A(p.Arg125His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00119 in 1,613,954 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R125L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00082 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (43 hom.)
• Consequence: CYP2C9 NM_000771.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.78

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.023801684).
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000821 (125/152254) while in subpopulation SAS AF= 0.0207 (100/4820). AF 95% confidence interval is 0.0175. There are 2 homozygotes in gnomad4. There are 95 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 126 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP2C9	NM_000771.4	c.374G>A	p.Arg125His	missense_variant	3/9	ENST00000260682.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP2C9	ENST00000260682.8	c.374G>A	p.Arg125His	missense_variant	3/9	1	NM_000771.4	P1

Frequencies

GnomAD3 genomes AF: 0.000828 AC: 126 AN: 152136 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.0209

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00243 AC: 610 AN: 251246 Hom.: 14 AF XY: 0.00355 AC XY: 482 AN XY: 135778

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0188

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000123

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.00122 AC: 1790 AN: 1461700 Hom.: 43 Cov.: 33 AF XY: 0.00181 AC XY: 1316 AN XY: 727156

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.000179

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0187

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000782

Gnomad4 OTH exome AF: 0.00106

GnomAD4 genome AF: 0.000821 AC: 125 AN: 152254 Hom.: 2 Cov.: 32 AF XY: 0.00128 AC XY: 95 AN XY: 74430

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.0207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000371 Hom.: 0

Bravo AF: 0.000314

ExAC AF: 0.00295 AC: 358

EpiCase AF: 0.000164

EpiControl AF: 0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Aug 21, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.41
Cadd	Benign	20
Dann	Uncertain	1.0
Eigen	Benign	0.11
Eigen_PC	Benign	-0.023
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.78	T;T
MetaRNN	Benign	0.024	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Pathogenic	3.3	M;M
MutationTaster	Benign	0.96	D
PrimateAI	Benign	0.32	T
Polyphen		0.76	.;P
Vest4		0.37
MutPred		0.81		Loss of phosphorylation at S127 (P = 0.0594);Loss of phosphorylation at S127 (P = 0.0594);
MVP		0.52
MPC		0.017
ClinPred		0.17	T
GERP RS		2.4
Varity_R		0.29
gMVP		0.14

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

LitVar

Other links and lift over

dbSNP: rs72558189; hg19: chr10-96701991;