10-94762706-A-G

Variant names:

• chr10-94762706-A-G
• rs28399504
• NM_000769.4:c.1A>G

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PVS1_Supporting BS2

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
• Clinical Significance: drug response practice guideline B:1 O:3
• Conservation: PhyloP100: 0.495
• Publications: 182 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: Likely_benign. The variant received -3 ACMG points.

• PVS1: Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 74 codons. Genomic position: 94775109. Lost 0.149 part of the original CDS.
• BS2: High AC in GnomAd4 at 362 AD gene.

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.1A>G	p.Met1?	start_lost	Exon 1 of 9	NP_000760.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP2C19	ENST00000371321.9	TSL:1 MANE Select	c.1A>G	p.Met1?	start_lost	Exon 1 of 9	ENSP00000360372.3
	CYP2C19	ENST00000480405.2	TSL:1	c.1A>G	p.Met1?	start_lost	Exon 1 of 3	ENSP00000483847.1
	ENSG00000276490	ENST00000464755.1	TSL:2	n.932-12352A>G		intron	N/A	ENSP00000483243.1

Frequencies

GnomAD3 genomes AF: 0.00238 AC: 362 AN: 152162 Hom.: 2 Cov.: 33

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

GnomAD2 exomes AF: 0.00233 AC: 585 AN: 251032 AF XY: 0.00226

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 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.: 14 Cov.: 30 AF XY: 0.00243 AC XY: 1769 AN XY: 726674

African (AFR) AF: 0.000419 AC: 14 AN: 33450

American (AMR) AF: 0.00286 AC: 128 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.0164 AC: 428 AN: 26092

East Asian (EAS) AF: 0.000252 AC: 10 AN: 39678

South Asian (SAS) AF: 0.000290 AC: 25 AN: 86204

European-Finnish (FIN) AF: 0.0000562 AC: 3 AN: 53352

Middle Eastern (MID) AF: 0.00110 AC: 6 AN: 5464

European-Non Finnish (NFE) AF: 0.00244 AC: 2712 AN: 1111568

Other (OTH) AF: 0.00295 AC: 178 AN: 60338

GnomAD4 genome AF: 0.00238 AC: 362 AN: 152280 Hom.: 2 Cov.: 33 AF XY: 0.00267 AC XY: 199 AN XY: 74442

African (AFR) AF: 0.000553 AC: 23 AN: 41588

American (AMR) AF: 0.00647 AC: 99 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0158 AC: 55 AN: 3472

East Asian (EAS) AF: 0.000579 AC: 3 AN: 5180

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4822

European-Finnish (FIN) AF: 0.0000946 AC: 1 AN: 10568

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00256 AC: 174 AN: 68018

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.00286 Hom.: 11

Bravo AF: 0.00247

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00326 AC: 28

ExAC AF: 0.00189 AC: 229

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00218

EpiControl AF: 0.00279

ClinVar

Significance: drug response

Submissions summary: Benign:1 Other:3

Revision: practice guideline

Submissions by phenotype

not provided Benign:1 Other:1

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.

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).

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	15
DANN	Benign	0.79
DEOGEN2	Benign	0.062	T
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.17	N
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.014	T
MetaSVM	Benign	-0.70	T
PhyloP100		0.49
PROVEAN	Uncertain	-3.4	D
REVEL	Uncertain	0.31
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.016	D
Vest4		0.49
MVP		0.61
ClinPred		0.060	T
GERP RS		1.8
PromoterAI		0.047	Neutral
gMVP		0.33
Mutation Taster		=114/86	polymorphism

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

Other links and lift over

dbSNP: rs28399504; hg19: chr10-96522463;