10-94780653-G-A

Variant names:

• chr10-94780653-G-A
• rs4986893
• NM_000769.4:c.636G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_000769.4(CYP2C19):​c.636G>A​(p.Trp212*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00294 in 1,613,588 control chromosomes in the GnomAD database, including 214 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as drug response (★★★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0025 (13 hom., cov: 32)
  • Exomes 𝑓: 0.0030 (201 hom.)
• Consequence: CYP2C19 NM_000769.4 stop_gained
• Clinical Significance: drug response practice guideline B:1 O:6
• Conservation: PhyloP100: 4.14
• Publications: 673 publications found

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

Our verdict: Benign. The variant received -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0554 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000769.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP2C19	NM_000769.4	MANE Select	c.636G>A	p.Trp212*	stop_gained	Exon 4 of 9	NP_000760.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP2C19	ENST00000371321.9	TSL:1 MANE Select	c.636G>A	p.Trp212*	stop_gained	Exon 4 of 9	ENSP00000360372.3
	ENSG00000276490	ENST00000464755.1	TSL:2	n.*394G>A		non_coding_transcript_exon	Exon 9 of 14	ENSP00000483243.1
	ENSG00000276490	ENST00000464755.1	TSL:2	n.*394G>A		3_prime_UTR	Exon 9 of 14	ENSP00000483243.1

Frequencies

GnomAD3 genomes AF: 0.00251 AC: 381 AN: 152056 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0610

Gnomad SAS AF: 0.00518

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00538 AC: 1351 AN: 251142 AF XY: 0.00507

Gnomad AFR exome AF: 0.000370

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0636

Gnomad FIN exome AF: 0.0000925

Gnomad NFE exome AF: 0.000246

Gnomad OTH exome AF: 0.00261

GnomAD4 exome AF: 0.00298 AC: 4362 AN: 1461412 Hom.: 201 Cov.: 31 AF XY: 0.00303 AC XY: 2204 AN XY: 727026

African (AFR) AF: 0.000538 AC: 18 AN: 33442

American (AMR) AF: 0.000179 AC: 8 AN: 44674

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.0923 AC: 3662 AN: 39672

South Asian (SAS) AF: 0.00340 AC: 293 AN: 86240

European-Finnish (FIN) AF: 0.000131 AC: 7 AN: 53358

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5762

European-Non Finnish (NFE) AF: 0.000101 AC: 112 AN: 1111770

Other (OTH) AF: 0.00421 AC: 254 AN: 60378

GnomAD4 genome AF: 0.00255 AC: 388 AN: 152176 Hom.: 13 Cov.: 32 AF XY: 0.00273 AC XY: 203 AN XY: 74362

African (AFR) AF: 0.000385 AC: 16 AN: 41550

American (AMR) AF: 0.000523 AC: 8 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.0610 AC: 315 AN: 5168

South Asian (SAS) AF: 0.00498 AC: 24 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10550

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 68004

Other (OTH) AF: 0.00614 AC: 13 AN: 2116

Alfa AF: 0.00555 Hom.: 875

Bravo AF: 0.00267

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00549 AC: 667

Asia WGS AF: 0.0460 AC: 160 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000178

ClinVar

ClinVar submissions as Germline

Significance: drug response

Revision: practice guideline

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (2)
-	-	-	Acute coronary syndrome (1)
-	-	-	Clopidogrel response (1)
-	-	-	CYP2C19: no function (1)
-	-	-	Mephenytoin, poor metabolism of (1)
-	-	-	Proguanil, poor metabolism of (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.069	T
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	35
DANN	Uncertain	0.98
Eigen	Benign	0.18
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.052	N
PhyloP100		4.1
Vest4		0.79
GERP RS		3.3
Mutation Taster		=145/55	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4986893; hg19: chr10-96540410; COSMIC: COSV64907205; COSMIC: COSV64907205;