Genetic Variant NM_000769.4:c.146A>T (chr10-94762851-A-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_000769.4(CYP2C19):c.146A>T(p.Asp49Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CYP2C19
NM_000769.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.62

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 made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.40718096).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP2C19	NM_000769.4 link	c.146A>T	p.Asp49Val	missense_variant	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.146A>T	p.Asp49Val	missense_variant	Exon 1 of 9	1	NM_000769.4	ENSP00000360372.3	P33261
CYP2C19	ENST00000480405.2 link	c.146A>T	p.Asp49Val	missense_variant	Exon 1 of 3	1		ENSP00000483847.1	A0A087X125
ENSG00000276490	ENST00000464755.1 link	n.932-12207A>T		intron_variant	Intron 6 of 13	2		ENSP00000483243.1	A0A087X0B3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251246

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135796

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

6.84e-7

AC:

AN:

1461532

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727078

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 28, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.146A>T (p.D49V) alteration is located in exon 1 (coding exon 1) of the CYP2C19 gene. This alteration results from a A to T substitution at nucleotide position 146, causing the aspartic acid (D) at amino acid position 49 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.31

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.081

T;.

Eigen

Benign

-0.16

Eigen_PC

Benign

-0.32

FATHMM_MKL

Benign

0.27

LIST_S2

Benign

0.79

T;.

M_CAP

Benign

0.019

MetaRNN

Benign

0.41

T;T

MetaSVM

Benign

-0.78

PrimateAI

Benign

0.36

PROVEAN

Pathogenic

-6.3

.;D

REVEL

Benign

0.26

Sift

Uncertain

0.0010

.;D

Sift4G

Benign

0.099

T;T

Vest4

0.35

MutPred

0.53

Loss of disorder (P = 0.0416);Loss of disorder (P = 0.0416);

MVP

0.77

MPC

0.011

ClinPred

0.88

GERP RS

4.2

gMVP

0.45

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.12

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