10-94762608-T-C

Variant names:

• chr10-94762608-T-C
• rs4986894
• ENST00000464755.1:n.932-12450T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000464755.1(ENSG00000276490):​n.932-12450T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.163 in 1,232,090 control chromosomes in the GnomAD database, including 18,650 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 (2341 hom., cov: 32)
  • Exomes 𝑓: 0.16 (16309 hom.)
• Consequence: ENSG00000276490 ENST00000464755.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.514
• Publications: 44 publications found

Genes affected

ENSG00000276490 (HGNC:):

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

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.316 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000464755.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP2C19	NM_000769.4	MANE Select	c.-98T>C		upstream_gene	N/A	NP_000760.1	P33261

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENSG00000276490	ENST00000464755.1	TSL:2	n.932-12450T>C		intron	N/A	ENSP00000483243.1	A0A087X0B3
	CYP2C19	ENST00000371321.9	TSL:1 MANE Select	c.-98T>C		upstream_gene	N/A	ENSP00000360372.3	P33261
	CYP2C19	ENST00000480405.2	TSL:1	c.-98T>C		upstream_gene	N/A	ENSP00000483847.1	A0A087X125

Frequencies

GnomAD3 genomes AF: 0.166 AC: 25297 AN: 151964 Hom.: 2337 Cov.: 32

Gnomad AFR AF: 0.174

Gnomad AMI AF: 0.182

Gnomad AMR AF: 0.129

Gnomad ASJ AF: 0.132

Gnomad EAS AF: 0.312

Gnomad SAS AF: 0.328

Gnomad FIN AF: 0.185

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.147

Gnomad OTH AF: 0.147

GnomAD4 exome AF: 0.162 AC: 175358 AN: 1080008 Hom.: 16309 AF XY: 0.168 AC XY: 91270 AN XY: 544716

African (AFR) AF: 0.176 AC: 4427 AN: 25128

American (AMR) AF: 0.105 AC: 3790 AN: 36180

Ashkenazi Jewish (ASJ) AF: 0.133 AC: 2648 AN: 19904

East Asian (EAS) AF: 0.302 AC: 11322 AN: 37436

South Asian (SAS) AF: 0.323 AC: 22008 AN: 68224

European-Finnish (FIN) AF: 0.173 AC: 8700 AN: 50318

Middle Eastern (MID) AF: 0.111 AC: 356 AN: 3206

European-Non Finnish (NFE) AF: 0.144 AC: 114457 AN: 792878

Other (OTH) AF: 0.164 AC: 7650 AN: 46734

GnomAD4 genome AF: 0.166 AC: 25314 AN: 152082 Hom.: 2341 Cov.: 32 AF XY: 0.171 AC XY: 12672 AN XY: 74318

African (AFR) AF: 0.174 AC: 7206 AN: 41512

American (AMR) AF: 0.129 AC: 1972 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.132 AC: 457 AN: 3470

East Asian (EAS) AF: 0.312 AC: 1612 AN: 5166

South Asian (SAS) AF: 0.330 AC: 1586 AN: 4810

European-Finnish (FIN) AF: 0.185 AC: 1945 AN: 10510

Middle Eastern (MID) AF: 0.0816 AC: 24 AN: 294

European-Non Finnish (NFE) AF: 0.147 AC: 10025 AN: 68000

Other (OTH) AF: 0.152 AC: 321 AN: 2116

Alfa AF: 0.150 Hom.: 4946

Bravo AF: 0.159

Asia WGS AF: 0.303 AC: 1050 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	3.6
DANN	Benign	0.54
PhyloP100		0.51
PromoterAI		0.020	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4986894; hg19: chr10-96522365; COSMIC: COSV64908948;