Genetic Variant CYP2C19:p.Pro227Pro (chr10-94781859-G-T) – ACMG Classification: Likely_benign (-3 pts)

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2BP4_StrongBP7

The NM_000769.4(CYP2C19):c.681G>T(p.Pro227Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as drug response (no stars). Synonymous variant affecting the same amino acid position (i.e. P227P) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CYP2C19
NM_000769.4 synonymous

Scores

Clinical Significance

drug response no assertion criteria provided O:1

Conservation

PhyloP100: -0.801

Publications

1021 publications found

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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.89).

BP7

Synonymous conserved (PhyloP=-0.801 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP2C19	NM_000769.4 link	c.681G>T	p.Pro227Pro	synonymous_variant	Exon 5 of 9	ENST00000371321.9	NP_000760.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CYP2C19	ENST00000371321.9 link	c.681G>T	p.Pro227Pro	synonymous_variant	Exon 5 of 9	1	NM_000769.4	ENSP00000360372.3
ENSG00000276490	ENST00000464755.1 link	n.*439G>T		non_coding_transcript_exon_variant	Exon 10 of 14	2		ENSP00000483243.1
ENSG00000276490	ENST00000464755.1 link	n.*439G>T		3_prime_UTR_variant	Exon 10 of 14	2		ENSP00000483243.1
CYP2C19	ENST00000645461.1 link	n.1734G>T		non_coding_transcript_exon_variant	Exon 4 of 7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1316634

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

649744

African (AFR)

AF:

0.00

AC:

AN:

25948

American (AMR)

AF:

0.00

AC:

AN:

19668

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21662

East Asian (EAS)

AF:

0.00

AC:

AN:

31664

South Asian (SAS)

AF:

0.00

AC:

AN:

60802

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51032

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5324

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1046390

Other (OTH)

AF:

0.00

AC:

AN:

54144

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

4719

ClinVar

Significance: drug response

Submissions summary: Other:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Acute coronary syndrome

Other:1

Cardiology Department, The First Affiliated Hospital of Nanjing Medical University

Significance:drug response

Review Status:no assertion criteria provided

Collection Method:research

decreased function

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

1.8

(source)

DANN

Benign

0.37

PhyloP100

-0.80

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over