rs17882687

Positions:

• chr10-94762760-A-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Strong BS1 BS2

The NM_000769.4(CYP2C19):​c.55A>C​(p.Ile19Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00149 in 1,613,924 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as drug response (★★★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0058 (13 hom., cov: 33)
  • Exomes 𝑓: 0.0010 (11 hom.)
• Consequence: CYP2C19 NM_000769.4 missense
• Clinical Significance: drug response practice guideline B:1 O:1
• Conservation: PhyloP100: -0.464

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009020865).
• BP6: Variant 10-94762760-A-C is Benign according to our data. Variant chr10-94762760-A-C is described in ClinVar as [drug_response]. Clinvar id is 633881.Status of the report is practice_guideline, 4 stars. We mark this variant Likely_benign, oryginal submissions are: {Benign=1, drug_response=1}. Variant chr10-94762760-A-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00581 (885/152226) while in subpopulation AFR AF= 0.0192 (796/41556). AF 95% confidence interval is 0.0181. There are 13 homozygotes in gnomad4. There are 425 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 885 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP2C19	NM_000769.4	c.55A>C	p.Ile19Leu	missense_variant	1/9	ENST00000371321.9	NP_000760.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP2C19	ENST00000371321.9	c.55A>C	p.Ile19Leu	missense_variant	1/9	1	NM_000769.4	ENSP00000360372	P1
CYP2C19	ENST00000480405.2	c.55A>C	p.Ile19Leu	missense_variant	1/3	1		ENSP00000483847

Frequencies

GnomAD3 genomes AF: 0.00573 AC: 872 AN: 152108 Hom.: 10 Cov.: 33

Gnomad AFR AF: 0.0189

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00223

Gnomad ASJ AF: 0.00404

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.000441

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00176 AC: 443 AN: 251250 Hom.: 1 AF XY: 0.00137 AC XY: 186 AN XY: 135788

Gnomad AFR exome AF: 0.0195

Gnomad AMR exome AF: 0.000868

Gnomad ASJ exome AF: 0.00397

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000361

Gnomad OTH exome AF: 0.00180

GnomAD4 exome AF: 0.00104 AC: 1520 AN: 1461698 Hom.: 11 Cov.: 30 AF XY: 0.000970 AC XY: 705 AN XY: 727144

Gnomad4 AFR exome AF: 0.0221

Gnomad4 AMR exome AF: 0.00103

Gnomad4 ASJ exome AF: 0.00436

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000139

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.000402

Gnomad4 OTH exome AF: 0.00230

GnomAD4 genome AF: 0.00581 AC: 885 AN: 152226 Hom.: 13 Cov.: 33 AF XY: 0.00571 AC XY: 425 AN XY: 74422

Gnomad4 AFR AF: 0.0192

Gnomad4 AMR AF: 0.00222

Gnomad4 ASJ AF: 0.00404

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000441

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00329 Hom.: 0

Bravo AF: 0.00674

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0195 AC: 86

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00213 AC: 258

Asia WGS AF: 0.00491 AC: 17 AN: 3478

EpiCase AF: 0.000600

EpiControl AF: 0.000415

ClinVar

Significance: drug response

Submissions summary: Benign:1 Other:1

Revision: practice guideline

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 17, 2018

- -

CYP2C19: normal function Other:1

drug response, practice guideline

curation

Clinical Pharmacogenetics Implementation Consortium

-

- Allele function

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	0.17
DANN	Benign	0.45
DEOGEN2	Benign	0.0023	T;.
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.0011	N
LIST_S2	Benign	0.0092	T;.
MetaRNN	Benign	0.0090	T;T
MetaSVM	Benign	-0.94	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.39	T
PROVEAN	Benign	1.4	.;N
REVEL	Benign	0.091
Sift	Benign	1.0	.;T
Sift4G	Benign	1.0	T;T
Vest4		0.078
MVP		0.19
MPC		0.0054
ClinPred		0.0028	T
GERP RS		-4.0
gMVP		0.094

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs17882687; hg19: chr10-96522517;