10-94842866-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000769.4(CYP2C19):c.991A>G(p.Ile331Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.939 in 1,614,130 control chromosomes in the GnomAD database, including 711,604 homozygotes. In-silico tool predicts a benign outcome for this variant. 5/6 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.95 (69116 hom., cov: 32)
  • Exomes 𝑓: 0.94 (642488 hom.)
• Consequence: CYP2C19 NM_000769.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.10

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0051977336).
• BP6: Variant 10-94842866-A-G is Benign according to our data. Variant chr10-94842866-A-G is described in ClinVar as [Benign]. Clinvar id is 39354.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr10-94842866-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.98 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP2C19	NM_000769.4	c.991A>G	p.Ile331Val	missense_variant	7/9	ENST00000371321.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP2C19	ENST00000371321.9	c.991A>G	p.Ile331Val	missense_variant	7/9	1	NM_000769.4	P1
CYP2C19	ENST00000645461.1	n.1902A>G		non_coding_transcript_exon_variant	5/7

Frequencies

GnomAD3 genomes AF: 0.952 AC: 144900 AN: 152166 Hom.: 69051 Cov.: 32

Gnomad AFR AF: 0.987

Gnomad AMI AF: 0.970

Gnomad AMR AF: 0.954

Gnomad ASJ AF: 0.920

Gnomad EAS AF: 0.962

Gnomad SAS AF: 0.886

Gnomad FIN AF: 0.949

Gnomad MID AF: 0.927

Gnomad NFE AF: 0.937

Gnomad OTH AF: 0.946

GnomAD4 exome AF: 0.937 AC: 1370162 AN: 1461846 Hom.: 642488 Cov.: 61 AF XY: 0.936 AC XY: 680578 AN XY: 727226

Gnomad4 AFR exome AF: 0.988

Gnomad4 AMR exome AF: 0.962

Gnomad4 ASJ exome AF: 0.918

Gnomad4 EAS exome AF: 0.960

Gnomad4 SAS exome AF: 0.890

Gnomad4 FIN exome AF: 0.943

Gnomad4 NFE exome AF: 0.938

Gnomad4 OTH exome AF: 0.939

GnomAD4 genome AF: 0.952 AC: 145025 AN: 152284 Hom.: 69116 Cov.: 32 AF XY: 0.952 AC XY: 70850 AN XY: 74442

Gnomad4 AFR AF: 0.988

Gnomad4 AMR AF: 0.954

Gnomad4 ASJ AF: 0.920

Gnomad4 EAS AF: 0.962

Gnomad4 SAS AF: 0.885

Gnomad4 FIN AF: 0.949

Gnomad4 NFE AF: 0.937

Gnomad4 OTH AF: 0.948

Alfa AF: 0.941 Hom.: 29064

Bravo AF: 0.956

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

May 12, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_noAF	Benign	-0.90
Cadd	Benign	0.0070
MetaRNN	Benign	0.0052	T
Sift4G	Benign	0.35	T
Vest4		0.17
gMVP		0.055

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs3758581; hg19: chr10-96602623;