10-94842866-A-G

Variant names:

• chr10-94842866-A-G
• rs3758581
• NM_000769.4:c.991A>G

Variant summary

Our verdict is Benign. The variant received -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 (★).

• 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
• Publications: 100 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 -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 VariationId is 39354.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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 rank	MANE	Protein	UniProt
CYP2C19	NM_000769.4	c.991A>G	p.Ile331Val	missense_variant	Exon 7 of 9	ENST00000371321.9	NP_000760.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP2C19	ENST00000371321.9	c.991A>G	p.Ile331Val	missense_variant	Exon 7 of 9	1	NM_000769.4	ENSP00000360372.3
ENSG00000276490	ENST00000464755.1	n.*749A>G		non_coding_transcript_exon_variant	Exon 12 of 14	2		ENSP00000483243.1
ENSG00000276490	ENST00000464755.1	n.*749A>G		3_prime_UTR_variant	Exon 12 of 14	2		ENSP00000483243.1
CYP2C19	ENST00000645461.1	n.1902A>G		non_coding_transcript_exon_variant	Exon 5 of 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

African (AFR) AF: 0.988 AC: 33058 AN: 33476

American (AMR) AF: 0.962 AC: 43032 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.918 AC: 23997 AN: 26136

East Asian (EAS) AF: 0.960 AC: 38103 AN: 39698

South Asian (SAS) AF: 0.890 AC: 76734 AN: 86250

European-Finnish (FIN) AF: 0.943 AC: 50372 AN: 53418

Middle Eastern (MID) AF: 0.927 AC: 5348 AN: 5768

European-Non Finnish (NFE) AF: 0.938 AC: 1042840 AN: 1111984

Other (OTH) AF: 0.939 AC: 56678 AN: 60392

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

African (AFR) AF: 0.988 AC: 41039 AN: 41556

American (AMR) AF: 0.954 AC: 14590 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.920 AC: 3193 AN: 3472

East Asian (EAS) AF: 0.962 AC: 4986 AN: 5182

South Asian (SAS) AF: 0.885 AC: 4274 AN: 4828

European-Finnish (FIN) AF: 0.949 AC: 10067 AN: 10604

Middle Eastern (MID) AF: 0.935 AC: 275 AN: 294

European-Non Finnish (NFE) AF: 0.937 AC: 63712 AN: 68026

Other (OTH) AF: 0.948 AC: 2004 AN: 2114

Alfa AF: 0.946 Hom.: 35590

Bravo AF: 0.956

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

May 12, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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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
PhyloP100		-1.1
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

Other links and lift over

dbSNP: rs3758581; hg19: chr10-96602623;