10-94775489-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BP6_Strong BS2

The NM_000769.4(CYP2C19):c.431G>A(p.Arg144His) variant causes a missense change. The variant allele was found at a frequency of 0.000707 in 1,614,010 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as drug response (★★★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R144S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0036 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00040 (5 hom.)
• Consequence: CYP2C19 NM_000769.4 missense
• Clinical Significance: drug response practice guideline B:1 O:1
• Conservation: PhyloP100: 3.83

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008557826).
• BP6: Variant 10-94775489-G-A is Benign according to our data. Variant chr10-94775489-G-A is described in ClinVar as [drug_response]. Clinvar id is 39352.Status of the report is practice_guideline, 4 stars. We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, drug_response=1}. Variant chr10-94775489-G-A is described in Lovd as [Likely_pathogenic].
• BS2: High AC in GnomAd at 543 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP2C19	NM_000769.4	c.431G>A	p.Arg144His	missense_variant	3/9	ENST00000371321.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP2C19	ENST00000371321.9	c.431G>A	p.Arg144His	missense_variant	3/9	1	NM_000769.4	P1
CYP2C19	ENST00000480405.2	c.431G>A	p.Arg144His	missense_variant	3/3	1
CYP2C19	ENST00000645461.1	n.1484G>A		non_coding_transcript_exon_variant	2/7

Frequencies

GnomAD3 genomes AF: 0.00357 AC: 543 AN: 152114 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.0125

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.000891 AC: 224 AN: 251418 Hom.: 0 AF XY: 0.000633 AC XY: 86 AN XY: 135876

Gnomad AFR exome AF: 0.0118

Gnomad AMR exome AF: 0.000636

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000405 AC: 592 AN: 1461778 Hom.: 5 Cov.: 31 AF XY: 0.000327 AC XY: 238 AN XY: 727186

Gnomad4 AFR exome AF: 0.0136

Gnomad4 AMR exome AF: 0.000738

Gnomad4 ASJ exome AF: 0.000153

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000243

Gnomad4 OTH exome AF: 0.00108

GnomAD4 genome AF: 0.00361 AC: 549 AN: 152232 Hom.: 2 Cov.: 33 AF XY: 0.00353 AC XY: 263 AN XY: 74444

Gnomad4 AFR AF: 0.0126

Gnomad4 AMR AF: 0.00118

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00194 Hom.: 0

Bravo AF: 0.00432

ESP6500AA AF: 0.0116 AC: 51

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00108 AC: 131

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: drug response

Submissions summary: Benign:1 Other:1

Revision: practice guideline

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 13, 2018

This variant is associated with the following publications: (PMID: 21325430, 12464799) -

CYP2C19: decreased 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
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.35
Cadd	Benign	20
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.072	T;.
Eigen	Benign	0.045
Eigen_PC	Benign	-0.083
FATHMM_MKL	Benign	0.52	D
LIST_S2	Benign	0.81	T;.
MetaRNN	Benign	0.0086	T;T
MetaSVM	Benign	-0.76	T
MutationTaster	Benign	0.98	N
PrimateAI	Benign	0.28	T
Sift4G	Uncertain	0.039	D;D
Vest4		0.13
MVP		0.73
MPC		0.019
ClinPred		0.064	T
GERP RS		3.0
gMVP		0.29

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: rs17884712; hg19: chr10-96535246; COSMIC: COSV100990619; COSMIC: COSV100990619;