chr15-74751198-C-T

Position:

• chr15-74751198-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The ENST00000343932.5(CYP1A2):​c.841C>T​(p.Arg281Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00149 in 1,613,996 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.00099 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (1 hom.)
• Consequence: CYP1A2 ENST00000343932.5 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.24

Genes affected

CYP1A2 (HGNC:2596): (cytochrome P450 family 1 subfamily A member 2) 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. The protein encoded by this gene localizes to the endoplasmic reticulum and its expression is induced by some polycyclic aromatic hydrocarbons (PAHs), some of which are found in cigarette smoke. The enzyme's endogenous substrate is unknown; however, it is able to metabolize some PAHs to carcinogenic intermediates. Other xenobiotic substrates for this enzyme include caffeine, aflatoxin B1, and acetaminophen. The transcript from this gene contains four Alu sequences flanked by direct repeats in the 3' untranslated region. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.060877055).
• BP6: Variant 15-74751198-C-T is Benign according to our data. Variant chr15-74751198-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 721012.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 150 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP1A2	NM_000761.5	c.841C>T	p.Arg281Trp	missense_variant	3/7	ENST00000343932.5	NP_000752.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP1A2	ENST00000343932.5	c.841C>T	p.Arg281Trp	missense_variant	3/7	1	NM_000761.5	ENSP00000342007	P1

Frequencies

GnomAD3 genomes AF: 0.000986 AC: 150 AN: 152100 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000266

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00148

Gnomad OTH AF: 0.00384

GnomAD3 exomes AF: 0.00118 AC: 297 AN: 251104 Hom.: 0 AF XY: 0.00125 AC XY: 169 AN XY: 135708

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.00208

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.000272

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00164

Gnomad OTH exome AF: 0.00277

GnomAD4 exome AF: 0.00154 AC: 2254 AN: 1461778 Hom.: 1 Cov.: 31 AF XY: 0.00150 AC XY: 1092 AN XY: 727208

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.00201

Gnomad4 ASJ exome AF: 0.000306

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.000187

Gnomad4 NFE exome AF: 0.00184

Gnomad4 OTH exome AF: 0.00129

GnomAD4 genome AF: 0.000985 AC: 150 AN: 152218 Hom.: 0 Cov.: 32 AF XY: 0.00102 AC XY: 76 AN XY: 74420

Gnomad4 AFR AF: 0.000265

Gnomad4 AMR AF: 0.00164

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00148

Gnomad4 OTH AF: 0.00380

Alfa AF: 0.00160 Hom.: 0

Bravo AF: 0.00125

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000228 AC: 1

ESP6500EA AF: 0.00140 AC: 12

ExAC AF: 0.00112 AC: 136

EpiCase AF: 0.00185

EpiControl AF: 0.00213

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 10, 2018	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.25
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.75	D
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.081	D
MetaRNN	Benign	0.061	T
MetaSVM	Uncertain	0.41	D
MutationAssessor	Pathogenic	3.0	M
MutationTaster	Benign	0.94	D
PrimateAI	Benign	0.28	T
PROVEAN	Pathogenic	-6.3	D
REVEL	Uncertain	0.47
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.43
MVP		0.86
MPC		0.31
ClinPred		0.057	T
GERP RS		3.9
Varity_R		0.74
gMVP		0.60

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

Publications

LitVar

Other links and lift over

dbSNP: rs45468096; hg19: chr15-75043539;