Genetic Variant NM_000769.4:c.169-231G>A (chr10-94774827-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000769.4(CYP2C19):c.169-231G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.459 in 537,854 control chromosomes in the GnomAD database, including 59,258 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.48 ( 18849 hom., cov: 32)

Exomes 𝑓: 0.45 ( 40409 hom. )

Consequence

CYP2C19
NM_000769.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.424

Publications

18 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:

MTND4P19 (HGNC:42206): (MT-ND4 pseudogene 19)

MTND4P19 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-1.0).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.629 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP2C19	NM_000769.4 link	c.169-231G>A		intron_variant	Intron 1 of 8	ENST00000371321.9	NP_000760.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP2C19	ENST00000371321.9 link	c.169-231G>A		intron_variant	Intron 1 of 8	1	NM_000769.4	ENSP00000360372.3
ENSG00000276490	ENST00000464755.1 link	n.932-231G>A		intron_variant	Intron 6 of 13	2		ENSP00000483243.1

Frequencies

GnomAD3 genomes

AF:

0.485

AC:

73589

AN:

151846

Hom.:

18830

Cov.:

show subpopulations

Gnomad AFR

AF:

0.636

Gnomad AMI

AF:

0.476

Gnomad AMR

AF:

0.335

Gnomad ASJ

AF:

0.431

Gnomad EAS

AF:

0.421

Gnomad SAS

AF:

0.616

Gnomad FIN

AF:

0.423

Gnomad MID

AF:

0.421

Gnomad NFE

AF:

0.435

Gnomad OTH

AF:

0.457

GnomAD4 exome

AF:

0.449

AC:

173259

AN:

385890

Hom.:

40409

Cov.:

AF XY:

0.458

AC XY:

92972

AN XY:

202870

show subpopulations

African (AFR)

AF:

0.636

AC:

7208

AN:

11334

American (AMR)

AF:

0.288

AC:

4385

AN:

15214

Ashkenazi Jewish (ASJ)

AF:

0.433

AC:

5187

AN:

11974

East Asian (EAS)

AF:

0.448

AC:

11908

AN:

26600

South Asian (SAS)

AF:

0.608

AC:

23253

AN:

38228

European-Finnish (FIN)

AF:

0.423

AC:

9861

AN:

23328

Middle Eastern (MID)

AF:

0.410

AC:

700

AN:

1708

European-Non Finnish (NFE)

AF:

0.429

AC:

100941

AN:

235048

Other (OTH)

AF:

0.437

AC:

9816

AN:

22456

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

4367

8734

13100

17467

21834

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

614

1228

1842

2456

3070

<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:

0.485

AC:

73653

AN:

151964

Hom.:

18849

Cov.:

AF XY:

0.485

AC XY:

35978

AN XY:

74238

show subpopulations

African (AFR)

AF:

0.636

AC:

26363

AN:

41470

American (AMR)

AF:

0.335

AC:

5113

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.431

AC:

1495

AN:

3466

East Asian (EAS)

AF:

0.420

AC:

2173

AN:

5168

South Asian (SAS)

AF:

0.616

AC:

2970

AN:

4818

European-Finnish (FIN)

AF:

0.423

AC:

4433

AN:

10484

Middle Eastern (MID)

AF:

0.412

AC:

121

AN:

294

European-Non Finnish (NFE)

AF:

0.435

AC:

29576

AN:

67956

Other (OTH)

AF:

0.461

AC:

975

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1876

3752

5628

7504

9380

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

664

1328

1992

2656

3320

<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:

0.451

Hom.:

53526

Bravo

AF:

0.478

Asia WGS

AF:

0.533

AC:

1853

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-1.0

CADD

Benign

0.53

(source)

DANN

Benign

0.27

PhyloP100

-0.42

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

Computational scores

Splicing

Publications

Other links and lift over