NM_000769.4:c.1A>G

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PVS1_ModerateBP6_StrongBS2

The NM_000769.4(CYP2C19):c.1A>G(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0024 in 1,613,130 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as drug response (★★★★).

Frequency

Genomes: 𝑓 0.0024 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0024 ( 14 hom. )

Consequence

CYP2C19
NM_000769.4 start_lost

Scores

Clinical Significance

drug response practice guideline B:1O:3

Conservation

PhyloP100: 0.495

Variant links:

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]

CYP2C19 links:

ENSG00000276490 (HGNC:):

ENSG00000276490 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

PVS1

Start lost variant, next in-frame start position is after 1 pathogenic variants. Next in-frame start position is after 74 codons. Genomic position: 94775109. Lost 0.149 part of the original CDS.

BP6

Variant 10-94762706-A-G is Benign according to our data. Variant chr10-94762706-A-G is described in ClinVar as [drug_response]. Clinvar id is 16900.Status of the report is practice_guideline, 4 stars. We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, drug_response=1, other=1}. Variant chr10-94762706-A-G is described in Lovd as [Pathogenic].

BS2

High AC in GnomAd4 at 362 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP2C19	NM_000769.4 link	c.1A>G	p.Met1?	start_lost	Exon 1 of 9	ENST00000371321.9	NP_000760.1	P33261

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CYP2C19	ENST00000371321.9 link	c.1A>G	p.Met1?	start_lost	Exon 1 of 9	1	NM_000769.4	ENSP00000360372.3	P33261
CYP2C19	ENST00000480405.2 link	c.1A>G	p.Met1?	start_lost	Exon 1 of 3	1		ENSP00000483847.1	A0A087X125
ENSG00000276490	ENST00000464755.1 link	n.932-12352A>G		intron_variant	Intron 6 of 13	2		ENSP00000483243.1	A0A087X0B3

Frequencies

GnomAD3 genomes

AF:

0.00238

AC:

362

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000555

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00647

Gnomad ASJ

AF:

0.0158

Gnomad EAS

AF:

0.000578

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.0000946

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00256

Gnomad OTH

AF:

0.000955

GnomAD3 exomes

AF:

0.00233

AC:

585

AN:

251032

Hom.:

AF XY:

0.00226

AC XY:

306

AN XY:

135666

show subpopulations

Gnomad AFR exome

AF:

0.000369

Gnomad AMR exome

AF:

0.00287

Gnomad ASJ exome

AF:

0.0162

Gnomad EAS exome

AF:

0.000381

Gnomad SAS exome

AF:

0.000262

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00251

Gnomad OTH exome

AF:

0.00278

GnomAD4 exome

AF:

0.00240

AC:

3504

AN:

1460850

Hom.:

Cov.:

AF XY:

0.00243

AC XY:

1769

AN XY:

726674

show subpopulations

Gnomad4 AFR exome

AF:

0.000419

Gnomad4 AMR exome

AF:

0.00286

Gnomad4 ASJ exome

AF:

0.0164

Gnomad4 EAS exome

AF:

0.000252

Gnomad4 SAS exome

AF:

0.000290

Gnomad4 FIN exome

AF:

0.0000562

Gnomad4 NFE exome

AF:

0.00244

Gnomad4 OTH exome

AF:

0.00295

GnomAD4 genome

AF:

0.00238

AC:

362

AN:

152280

Hom.:

Cov.:

AF XY:

0.00267

AC XY:

199

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.000553

Gnomad4 AMR

AF:

0.00647

Gnomad4 ASJ

AF:

0.0158

Gnomad4 EAS

AF:

0.000579

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.0000946

Gnomad4 NFE

AF:

0.00256

Gnomad4 OTH

AF:

0.000945

Alfa

AF:

0.00312

Hom.:

Bravo

AF:

0.00247

TwinsUK

AF:

0.00216

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00326

AC:

ExAC

AF:

0.00189

AC:

229

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.00218

EpiControl

AF:

0.00279

ClinVar

Significance: drug response

Submissions summary: Benign:1Other:3

Revision: practice guideline

LINK: link

Submissions by phenotype

not provided

Benign:1Other:1

Dec 28, 2015

Eurofins Ntd Llc (ga)

Significance: other

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- Variant classified as "other reportable" ??? variant is clinically benign (not associated with disease) but is reported when observed (e.g. pseudodeficiency alleles).

Mar 26, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Mephenytoin, poor metabolism of

Other:1

Jan 01, 1998

OMIM

Significance: drug response

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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 v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.26

CADD

Benign

DANN

Benign

0.79

DEOGEN2

Benign

0.062

T;.

Eigen

Benign

-0.37

Eigen_PC

Benign

-0.57

FATHMM_MKL

Benign

0.17

LIST_S2

Uncertain

0.90

D;.

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.014

T;T

MetaSVM

Benign

-0.70

PROVEAN

Uncertain

-3.4

.;D

REVEL

Uncertain

0.31

Sift

Uncertain

0.0010

.;D

Sift4G

Uncertain

0.016

D;D

Vest4

0.49

MVP

0.61

ClinPred

0.060

GERP RS

1.8

gMVP

0.33

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over