10-94775165-G-C

Position:

• chr10-94775165-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_000769.4(CYP2C19):​c.276G>C​(p.Glu92Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0282 in 1,614,098 control chromosomes in the GnomAD database, including 763 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.022 (46 hom., cov: 32)
  • Exomes 𝑓: 0.029 (717 hom.)
• Consequence: CYP2C19 NM_000769.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.10

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]

ENSG00000276490 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004840821).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0218 (3315/152236) while in subpopulation NFE AF= 0.0316 (2146/68012). AF 95% confidence interval is 0.0304. There are 46 homozygotes in gnomad4. There are 1560 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 3315 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP2C19	NM_000769.4	c.276G>C	p.Glu92Asp	missense_variant	2/9	ENST00000371321.9	NP_000760.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP2C19	ENST00000371321.9	c.276G>C	p.Glu92Asp	missense_variant	2/9	1	NM_000769.4	ENSP00000360372.3
ENSG00000276490	ENST00000464755.1	n.*34G>C		non_coding_transcript_exon_variant	7/14	2		ENSP00000483243.1
ENSG00000276490	ENST00000464755.1	n.*34G>C		3_prime_UTR_variant	7/14	2		ENSP00000483243.1

Frequencies

GnomAD3 genomes AF: 0.0218 AC: 3317 AN: 152118 Hom.: 46 Cov.: 32

Gnomad AFR AF: 0.00840

Gnomad AMI AF: 0.0504

Gnomad AMR AF: 0.0165

Gnomad ASJ AF: 0.00606

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00848

Gnomad FIN AF: 0.0398

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0315

Gnomad OTH AF: 0.0177

GnomAD3 exomes AF: 0.0226 AC: 5675 AN: 251482 Hom.: 92 AF XY: 0.0227 AC XY: 3079 AN XY: 135910

Gnomad AFR exome AF: 0.00787

Gnomad AMR exome AF: 0.0151

Gnomad ASJ exome AF: 0.00655

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00800

Gnomad FIN exome AF: 0.0382

Gnomad NFE exome AF: 0.0327

Gnomad OTH exome AF: 0.0267

GnomAD4 exome AF: 0.0289 AC: 42253 AN: 1461862 Hom.: 717 Cov.: 31 AF XY: 0.0283 AC XY: 20580 AN XY: 727230

Gnomad4 AFR exome AF: 0.00672

Gnomad4 AMR exome AF: 0.0153

Gnomad4 ASJ exome AF: 0.00708

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00828

Gnomad4 FIN exome AF: 0.0398

Gnomad4 NFE exome AF: 0.0330

Gnomad4 OTH exome AF: 0.0248

GnomAD4 genome AF: 0.0218 AC: 3315 AN: 152236 Hom.: 46 Cov.: 32 AF XY: 0.0210 AC XY: 1560 AN XY: 74426

Gnomad4 AFR AF: 0.00837

Gnomad4 AMR AF: 0.0164

Gnomad4 ASJ AF: 0.00606

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00849

Gnomad4 FIN AF: 0.0398

Gnomad4 NFE AF: 0.0316

Gnomad4 OTH AF: 0.0175

Alfa AF: 0.0267 Hom.: 23

Bravo AF: 0.0200

TwinsUK AF: 0.0326 AC: 121

ALSPAC AF: 0.0291 AC: 112

ESP6500AA AF: 0.00862 AC: 38

ESP6500EA AF: 0.0305 AC: 262

ExAC AF: 0.0236 AC: 2865

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.0303

EpiControl AF: 0.0335

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	0.49
DANN	Benign	0.78
DEOGEN2	Benign	0.025	T;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.038	N
LIST_S2	Benign	0.68	T;.
MetaRNN	Benign	0.0048	T;T
MetaSVM	Benign	-1.1	T
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-2.1	.;N
REVEL	Benign	0.097
Sift	Benign	0.42	.;T
Sift4G	Benign	0.34	T;T
Vest4		0.057
MutPred		0.58		Loss of disorder (P = 0.1562);Loss of disorder (P = 0.1562);
MPC		0.0057
ClinPred		0.0089	T
GERP RS		-5.0
gMVP		0.24

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: rs17878459; hg19: chr10-96534922; COSMIC: COSV64908174; COSMIC: COSV64908174;