10-94762706-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 8P and 8B. PVS1 BP6_Strong 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

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 Uncertain_significance. Variant got 0 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• 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: {drug_response=1, other=1, Likely_benign=1}. Variant chr10-94762706-A-G is described in Lovd as [Pathogenic].
• BS2: High AC in GnomAd at 362 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP2C19	NM_000769.4	c.1A>G	p.Met1?	start_lost	1/9	ENST00000371321.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP2C19	ENST00000371321.9	c.1A>G	p.Met1?	start_lost	1/9	1	NM_000769.4	P1
CYP2C19	ENST00000480405.2	c.1A>G	p.Met1?	start_lost	1/3	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

GnomAD3 exomes AF: 0.00233 AC: 585 AN: 251032 Hom.: 4 AF XY: 0.00226 AC XY: 306 AN XY: 135666

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

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.: 2 Cov.: 33 AF XY: 0.00267 AC XY: 199 AN XY: 74442

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.: 10

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

other, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 28, 2015	- Variant classified as "other reportable" ??? variant is clinically benign (not associated with disease) but is reported when observed (e.g. pseudodeficiency alleles).
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 26, 2018	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

drug response, no assertion criteria provided

literature only

OMIM

Jan 01, 1998

- -

CYP2C19: no 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
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;T
MetaSVM	Benign	-0.70	T
MutationTaster	Benign	1.0	A
Sift4G	Uncertain	0.016	D;D
Vest4		0.49
MVP		0.61
ClinPred		0.060	T
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

Other links and lift over

dbSNP: rs28399504; hg19: chr10-96522463;