chr10-94775507-G-A

Position:

• chr10-94775507-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.449G>A​(p.Arg150His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00498 in 1,613,980 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 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.

• Frequency:
  • Genomes: 𝑓 0.0029 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0052 (26 hom.)
• Consequence: CYP2C19 NM_000769.4 missense
• Clinical Significance: drug response practice guideline B:1 O:1
• Conservation: PhyloP100: -1.42

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=0.005895734).
• BP6: Variant 10-94775507-G-A is Benign according to our data. Variant chr10-94775507-G-A is described in ClinVar as [drug_response]. Clinvar id is 633845.Status of the report is practice_guideline, 4 stars. We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, drug_response=1}.
• BS2: High AC in GnomAd4 at 440 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP2C19	NM_000769.4	c.449G>A	p.Arg150His	missense_variant	3/9	ENST00000371321.9	NP_000760.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP2C19	ENST00000371321.9	c.449G>A	p.Arg150His	missense_variant	3/9	1	NM_000769.4	ENSP00000360372	P1
CYP2C19	ENST00000480405.2	c.449G>A	p.Arg150His	missense_variant	3/3	1		ENSP00000483847
CYP2C19	ENST00000645461.1	n.1502G>A		non_coding_transcript_exon_variant	2/7

Frequencies

GnomAD3 genomes AF: 0.00289 AC: 439 AN: 152134 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00128

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.000661

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00528

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00269 AC: 676 AN: 251362 Hom.: 4 AF XY: 0.00277 AC XY: 376 AN XY: 135848

Gnomad AFR exome AF: 0.00117

Gnomad AMR exome AF: 0.000549

Gnomad ASJ exome AF: 0.000595

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000817

Gnomad FIN exome AF: 0.000416

Gnomad NFE exome AF: 0.00507

Gnomad OTH exome AF: 0.00359

GnomAD4 exome AF: 0.00520 AC: 7604 AN: 1461728 Hom.: 26 Cov.: 31 AF XY: 0.00501 AC XY: 3645 AN XY: 727166

Gnomad4 AFR exome AF: 0.00122

Gnomad4 AMR exome AF: 0.000514

Gnomad4 ASJ exome AF: 0.000612

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00106

Gnomad4 FIN exome AF: 0.000393

Gnomad4 NFE exome AF: 0.00643

Gnomad4 OTH exome AF: 0.00422

GnomAD4 genome AF: 0.00289 AC: 440 AN: 152252 Hom.: 5 Cov.: 32 AF XY: 0.00259 AC XY: 193 AN XY: 74438

Gnomad4 AFR AF: 0.00128

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.000661

Gnomad4 NFE AF: 0.00529

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00364 Hom.: 0

Bravo AF: 0.00280

TwinsUK AF: 0.00674 AC: 25

ALSPAC AF: 0.00441 AC: 17

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00535 AC: 46

ExAC AF: 0.00265 AC: 322

EpiCase AF: 0.00545

EpiControl AF: 0.00516

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

CeGaT Center for Human Genetics Tuebingen

Jan 01, 2024

CYP2C19: BP4, BS2 -

CYP2C19: normal 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	0.085
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	2.9
DANN	Benign	0.85
DEOGEN2	Benign	0.033	T;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0034	N
LIST_S2	Benign	0.032	T;.
M_CAP	Benign	0.0058	T
MetaRNN	Benign	0.0059	T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-1.4	.;N
REVEL	Benign	0.062
Sift	Benign	0.51	.;T
Sift4G	Benign	0.24	T;T
Vest4		0.034
MVP		0.26
MPC		0.0050
ClinPred		0.0020	T
GERP RS		-7.8
gMVP		0.17

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: rs58973490; hg19: chr10-96535264; COSMIC: COSV64909501; COSMIC: COSV64909501;