10-94775367-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000769.4(CYP2C19):c.332-23A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.165 in 1,612,890 control chromosomes in the GnomAD database, including 24,492 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as drug response (★★★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2548 hom., cov: 32)
  • Exomes 𝑓: 0.16 (21944 hom.)
• Consequence: CYP2C19 NM_000769.4 intron
• Clinical Significance: drug response practice guideline O:1
• Conservation: PhyloP100: 1.34

Genes affected

CYP2C19 (HGNC:2621): (cytochrome P450 family 2 subfamily C member 19) 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 is known to metabolize many xenobiotics, including the anticonvulsive drug mephenytoin, omeprazole, diazepam and some barbiturates. Polymorphism within this gene is associated with variable ability to metabolize mephenytoin, known as the poor metabolizer and extensive metabolizer phenotypes. 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 (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.318 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP2C19	NM_000769.4	c.332-23A>G		intron_variant		ENST00000371321.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP2C19	ENST00000371321.9	c.332-23A>G		intron_variant		1	NM_000769.4	P1
CYP2C19	ENST00000480405.2	c.332-23A>G		intron_variant		1
CYP2C19	ENST00000645461.1	n.1385-23A>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.173 AC: 26303 AN: 151746 Hom.: 2543 Cov.: 32

Gnomad AFR AF: 0.197

Gnomad AMI AF: 0.182

Gnomad AMR AF: 0.133

Gnomad ASJ AF: 0.133

Gnomad EAS AF: 0.312

Gnomad SAS AF: 0.330

Gnomad FIN AF: 0.185

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.148

Gnomad OTH AF: 0.152

GnomAD3 exomes AF: 0.180 AC: 45341 AN: 251244 Hom.: 4851 AF XY: 0.187 AC XY: 25439 AN XY: 135780

Gnomad AFR exome AF: 0.199

Gnomad AMR exome AF: 0.105

Gnomad ASJ exome AF: 0.134

Gnomad EAS exome AF: 0.310

Gnomad SAS exome AF: 0.327

Gnomad FIN exome AF: 0.173

Gnomad NFE exome AF: 0.147

Gnomad OTH exome AF: 0.157

GnomAD4 exome AF: 0.164 AC: 239816 AN: 1461026 Hom.: 21944 Cov.: 33 AF XY: 0.169 AC XY: 122657 AN XY: 726806

Gnomad4 AFR exome AF: 0.204

Gnomad4 AMR exome AF: 0.108

Gnomad4 ASJ exome AF: 0.134

Gnomad4 EAS exome AF: 0.303

Gnomad4 SAS exome AF: 0.324

Gnomad4 FIN exome AF: 0.173

Gnomad4 NFE exome AF: 0.148

Gnomad4 OTH exome AF: 0.168

GnomAD4 genome AF: 0.173 AC: 26324 AN: 151864 Hom.: 2548 Cov.: 32 AF XY: 0.177 AC XY: 13157 AN XY: 74166

Gnomad4 AFR AF: 0.196

Gnomad4 AMR AF: 0.133

Gnomad4 ASJ AF: 0.133

Gnomad4 EAS AF: 0.312

Gnomad4 SAS AF: 0.331

Gnomad4 FIN AF: 0.185

Gnomad4 NFE AF: 0.148

Gnomad4 OTH AF: 0.157

Alfa AF: 0.146 Hom.: 445

Bravo AF: 0.167

Asia WGS AF: 0.305 AC: 1059 AN: 3478

ClinVar

Significance: drug response

Submissions summary: Other:1

Revision: practice guideline

Submissions by phenotype

CYP2C19: no function Other:1

drug response, practice guideline

curation

Clinical Pharmacogenetics Implementation Consortium

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- Allele function

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	6.3
Dann	Benign	0.67
La Branchor		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs12769205; hg19: chr10-96535124; COSMIC: COSV64907469; COSMIC: COSV64907469;