dbSNP rs17886522: CYP2C19:p.Gly417Gly (chr10-94850018-A-C) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000769.4(CYP2C19):c.1251A>C(p.Gly417Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00406 in 1,613,662 control chromosomes in the GnomAD database, including 233 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0084 ( 22 hom., cov: 32)

Exomes 𝑓: 0.0036 ( 211 hom. )

Consequence

CYP2C19
NM_000769.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -2.31

Publications

16 publications found

Variant links:

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]

CYP2C19 links:

ENSG00000276490 (HGNC:):

ENSG00000276490 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BP6

Variant 10-94850018-A-C is Benign according to our data. Variant chr10-94850018-A-C is described in ClinVar as Benign. ClinVar VariationId is 1276601.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.31 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0557 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP2C19	NM_000769.4 link	c.1251A>C	p.Gly417Gly	synonymous_variant	Exon 8 of 9	ENST00000371321.9	NP_000760.1	P33261

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CYP2C19	ENST00000371321.9 link	c.1251A>C	p.Gly417Gly	synonymous_variant	Exon 8 of 9	1	NM_000769.4	ENSP00000360372.3	P33261
ENSG00000276490	ENST00000464755.1 link	n.*1009A>C		non_coding_transcript_exon_variant	Exon 13 of 14	2		ENSP00000483243.1	A0A087X0B3
ENSG00000276490	ENST00000464755.1 link	n.*1009A>C		3_prime_UTR_variant	Exon 13 of 14	2		ENSP00000483243.1	A0A087X0B3
CYP2C19	ENST00000645461.1 link	n.2162A>C		non_coding_transcript_exon_variant	Exon 6 of 7

Frequencies

GnomAD3 genomes

AF:

0.00831

AC:

1264

AN:

152118

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0208

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00184

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0613

Gnomad SAS

AF:

0.00518

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000250

Gnomad OTH

AF:

0.00765

GnomAD2 exomes

AF:

0.00680

AC:

1709

AN:

251204

AF XY:

0.00613

show subpopulations

Gnomad AFR exome

AF:

0.0206

Gnomad AMR exome

AF:

0.000753

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0636

Gnomad FIN exome

AF:

0.0000924

Gnomad NFE exome

AF:

0.000290

Gnomad OTH exome

AF:

0.00294

GnomAD4 exome

AF:

0.00361

AC:

5276

AN:

1461426

Hom.:

211

Cov.:

AF XY:

0.00359

AC XY:

2607

AN XY:

727000

show subpopulations

African (AFR)

AF:

0.0235

AC:

786

AN:

33452

American (AMR)

AF:

0.000694

AC:

AN:

44672

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26124

East Asian (EAS)

AF:

0.0924

AC:

3667

AN:

39676

South Asian (SAS)

AF:

0.00354

AC:

305

AN:

86248

European-Finnish (FIN)

AF:

0.000131

AC:

AN:

53408

Middle Eastern (MID)

AF:

0.00226

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.000118

AC:

131

AN:

1111716

Other (OTH)

AF:

0.00557

AC:

336

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

333

666

998

1331

1664

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

164

246

328

410

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00836

AC:

1273

AN:

152236

Hom.:

Cov.:

AF XY:

0.00845

AC XY:

629

AN XY:

74448

show subpopulations

African (AFR)

AF:

0.0208

AC:

864

AN:

41544

American (AMR)

AF:

0.00183

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.0612

AC:

316

AN:

5162

South Asian (SAS)

AF:

0.00498

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000250

AC:

AN:

68012

Other (OTH)

AF:

0.0114

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

126

189

252

315

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00552

Hom.:

Bravo

AF:

0.00875

Asia WGS

AF:

0.0460

AC:

161

AN:

3478

EpiCase

AF:

0.000327

EpiControl

AF:

0.000237

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 24, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

1.5

(source)

DANN

Benign

0.55

PhyloP100

-2.3

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over