10-94842865-C-T

Variant names:

• chr10-94842865-C-T
• rs3758580
• NM_000769.4:c.990C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_000769.4(CYP2C19):​c.990C>T​(p.Val330Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.164 in 1,613,896 control chromosomes in the GnomAD database, including 23,889 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 0.17 (2337 hom., cov: 31)
  • Exomes 𝑓: 0.16 (21552 hom.)
• Consequence: CYP2C19 NM_000769.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.690
• Publications: 44 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP7: Synonymous conserved (PhyloP=0.69 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.318 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP2C19	NM_000769.4	c.990C>T	p.Val330Val	synonymous_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.990C>T	p.Val330Val	synonymous_variant	Exon 7 of 9	1	NM_000769.4	ENSP00000360372.3
ENSG00000276490	ENST00000464755.1	n.*748C>T		non_coding_transcript_exon_variant	Exon 12 of 14	2		ENSP00000483243.1
ENSG00000276490	ENST00000464755.1	n.*748C>T		3_prime_UTR_variant	Exon 12 of 14	2		ENSP00000483243.1
CYP2C19	ENST00000645461.1	n.1901C>T		non_coding_transcript_exon_variant	Exon 5 of 7

Frequencies

GnomAD3 genomes AF: 0.167 AC: 25417 AN: 152032 Hom.: 2332 Cov.: 31

Gnomad AFR AF: 0.176

Gnomad AMI AF: 0.182

Gnomad AMR AF: 0.130

Gnomad ASJ AF: 0.131

Gnomad EAS AF: 0.313

Gnomad SAS AF: 0.330

Gnomad FIN AF: 0.183

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.147

Gnomad OTH AF: 0.148

GnomAD2 exomes AF: 0.178 AC: 44857 AN: 251338 AF XY: 0.186

Gnomad AFR exome AF: 0.178

Gnomad AMR exome AF: 0.103

Gnomad ASJ exome AF: 0.132

Gnomad EAS exome AF: 0.310

Gnomad FIN exome AF: 0.171

Gnomad NFE exome AF: 0.147

Gnomad OTH exome AF: 0.156

GnomAD4 exome AF: 0.163 AC: 238587 AN: 1461746 Hom.: 21552 Cov.: 31 AF XY: 0.168 AC XY: 122078 AN XY: 727194

African (AFR) AF: 0.182 AC: 6089 AN: 33474

American (AMR) AF: 0.105 AC: 4715 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.133 AC: 3486 AN: 26132

East Asian (EAS) AF: 0.303 AC: 12046 AN: 39696

South Asian (SAS) AF: 0.324 AC: 27933 AN: 86252

European-Finnish (FIN) AF: 0.171 AC: 9127 AN: 53414

Middle Eastern (MID) AF: 0.111 AC: 643 AN: 5768

European-Non Finnish (NFE) AF: 0.148 AC: 164503 AN: 1111900

Other (OTH) AF: 0.166 AC: 10045 AN: 60386

GnomAD4 genome AF: 0.167 AC: 25435 AN: 152150 Hom.: 2337 Cov.: 31 AF XY: 0.171 AC XY: 12747 AN XY: 74374

African (AFR) AF: 0.176 AC: 7309 AN: 41490

American (AMR) AF: 0.130 AC: 1980 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.131 AC: 456 AN: 3472

East Asian (EAS) AF: 0.312 AC: 1617 AN: 5178

South Asian (SAS) AF: 0.331 AC: 1597 AN: 4824

European-Finnish (FIN) AF: 0.183 AC: 1938 AN: 10584

Middle Eastern (MID) AF: 0.0850 AC: 25 AN: 294

European-Non Finnish (NFE) AF: 0.147 AC: 10026 AN: 68006

Other (OTH) AF: 0.152 AC: 321 AN: 2110

Alfa AF: 0.149 Hom.: 765

Bravo AF: 0.160

Asia WGS AF: 0.303 AC: 1051 AN: 3478

EpiCase AF: 0.149

EpiControl AF: 0.148

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.76
DANN	Benign	0.34
PhyloP100		0.69
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs3758580; hg19: chr10-96602622; COSMIC: COSV64906817;