10-94775106-C-T

Variant names:

• chr10-94775106-C-T
• rs145328984
• NM_000769.4:c.217C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_000769.4(CYP2C19):​c.217C>T​(p.Arg73Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000209 in 1,614,092 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as drug response (★★★★).

• Frequency:
  • Genomes: 𝑓 0.00088 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00014 (2 hom.)
• Consequence: CYP2C19 NM_000769.4 missense
• Clinical Significance: drug response practice guideline O:1
• Conservation: PhyloP100: 1.49
• Publications: 10 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.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0194951).
• BS2: High AC in GnomAd4 at 134 AD gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP2C19	NM_000769.4	MANE Select	c.217C>T	p.Arg73Cys	missense	Exon 2 of 9	NP_000760.1	P33261

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP2C19	ENST00000371321.9	TSL:1 MANE Select	c.217C>T	p.Arg73Cys	missense	Exon 2 of 9	ENSP00000360372.3	P33261
	CYP2C19	ENST00000480405.2	TSL:1	c.217C>T	p.Arg73Cys	missense	Exon 2 of 3	ENSP00000483847.1	A0A087X125
	ENSG00000276490	ENST00000464755.1	TSL:2	n.980C>T		non_coding_transcript_exon	Exon 7 of 14	ENSP00000483243.1	A0A087X0B3

Frequencies

GnomAD3 genomes AF: 0.000881 AC: 134 AN: 152112 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00285

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

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: 0.000191

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000266 AC: 67 AN: 251462 AF XY: 0.000213

Gnomad AFR exome AF: 0.00215

Gnomad AMR exome AF: 0.000434

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000140 AC: 204 AN: 1461862 Hom.: 2 Cov.: 31 AF XY: 0.000124 AC XY: 90 AN XY: 727230

African (AFR) AF: 0.00227 AC: 76 AN: 33480

American (AMR) AF: 0.000402 AC: 18 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39700

South Asian (SAS) AF: 0.000128 AC: 11 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.0000773 AC: 86 AN: 1112010

Other (OTH) AF: 0.000149 AC: 9 AN: 60396

GnomAD4 genome AF: 0.000880 AC: 134 AN: 152230 Hom.: 0 Cov.: 32 AF XY: 0.000860 AC XY: 64 AN XY: 74426

African (AFR) AF: 0.00284 AC: 118 AN: 41548

American (AMR) AF: 0.000196 AC: 3 AN: 15290

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10570

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

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.000429 Hom.: 0

Bravo AF: 0.000888

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00318 AC: 14

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000255 AC: 31

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: drug response

Revision: practice guideline

Pathogenic	VUS	Benign	Condition
-	-	-	CYP2C19: uncertain function (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.032	T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.48	N
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.0091	T
MetaRNN	Benign	0.019	T
MetaSVM	Benign	-1.0	T
PhyloP100		1.5
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.13
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.0020	D
Vest4		0.26
MVP		0.44
MPC		0.016
ClinPred		0.040	T
GERP RS		3.7
gMVP		0.42
Mutation Taster		=50/50

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: rs145328984; hg19: chr10-96534863; COSMIC: COSV64909462; COSMIC: COSV64909462;