10-94775367-A-G

Variant names:

• chr10-94775367-A-G
• rs12769205
• NM_000769.4:c.332-23A>G

Variant summary

Our verdict is Benign. The variant received -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 (★★★★). There are indicators that this mutation may affect the branch point..

• 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
• Publications: 60 publications found

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]

ENSG00000276490 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: This position, referring to a specific DNA site, is a probable branch point but rather VUS (scored 5 / 10). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000769.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP2C19	NM_000769.4	MANE Select	c.332-23A>G		intron	N/A	NP_000760.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP2C19	ENST00000371321.9	TSL:1 MANE Select	c.332-23A>G		intron	N/A	ENSP00000360372.3
	CYP2C19	ENST00000480405.2	TSL:1	c.332-23A>G		intron	N/A	ENSP00000483847.1
	ENSG00000276490	ENST00000464755.1	TSL:2	n.*90-23A>G		intron	N/A	ENSP00000483243.1

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

GnomAD2 exomes AF: 0.180 AC: 45341 AN: 251244 AF XY: 0.187

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 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

African (AFR) AF: 0.204 AC: 6818 AN: 33454

American (AMR) AF: 0.108 AC: 4815 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.134 AC: 3515 AN: 26136

East Asian (EAS) AF: 0.303 AC: 12034 AN: 39698

South Asian (SAS) AF: 0.324 AC: 27905 AN: 86220

European-Finnish (FIN) AF: 0.173 AC: 9242 AN: 53380

Middle Eastern (MID) AF: 0.116 AC: 597 AN: 5144

European-Non Finnish (NFE) AF: 0.148 AC: 164728 AN: 1111958

Other (OTH) AF: 0.168 AC: 10162 AN: 60316

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

African (AFR) AF: 0.196 AC: 8140 AN: 41466

American (AMR) AF: 0.133 AC: 2028 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.133 AC: 460 AN: 3470

East Asian (EAS) AF: 0.312 AC: 1610 AN: 5164

South Asian (SAS) AF: 0.331 AC: 1588 AN: 4796

European-Finnish (FIN) AF: 0.185 AC: 1934 AN: 10434

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.148 AC: 10041 AN: 67956

Other (OTH) AF: 0.157 AC: 330 AN: 2102

Alfa AF: 0.148 Hom.: 3143

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

Clinical Pharmacogenetics Implementation Consortium

Significance: drug response

Review Status: practice guideline

Collection Method: curation

Allele function

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	6.3
DANN	Benign	0.67
PhyloP100		1.3
La Branchor		0.73
BranchPoint Hunter		5.0
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs12769205; hg19: chr10-96535124; COSMIC: COSV64907469; COSMIC: COSV64907469;