Genetic Variant CYP2A13:p.His164Arg (chr19-41090194-A-G) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_000766.5(CYP2A13):c.491A>G(p.His164Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000842 in 1,425,192 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000084 ( 0 hom. )

Consequence

CYP2A13
NM_000766.5 missense, splice_region

Scores

Splicing: ADA: 0.00008201

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -1.18

Variant links:

Genes affected

CYP2A13 (HGNC:2608): (cytochrome P450 family 2 subfamily A member 13) 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. Although its endogenous substrate has not been determined, it is known to metabolize 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, a major nitrosamine specific to tobacco. This gene is part of a large cluster of cytochrome P450 genes from the CYP2A, CYP2B and CYP2F subfamilies on chromosome 19q. [provided by RefSeq, Jul 2008]

CYP2A13 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.020071149).

BP6

Variant 19-41090194-A-G is Benign according to our data. Variant chr19-41090194-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 2378264.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP2A13	NM_000766.5 link	c.491A>G	p.His164Arg	missense_variant, splice_region_variant	Exon 3 of 9	ENST00000330436.4	NP_000757.2	Q16696

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP2A13	ENST00000330436.4 link	c.491A>G	p.His164Arg	missense_variant, splice_region_variant	Exon 3 of 9	1	NM_000766.5	ENSP00000332679.1		Q16696

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000505

AC:

AN:

217656

Hom.:

AF XY:

0.0000344

AC XY:

AN XY:

116120

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000320

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000101

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000842

AC:

AN:

1425192

Hom.:

Cov.:

AF XY:

0.00000710

AC XY:

AN XY:

704672

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000217

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000274

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Nov 08, 2022

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.054

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.81

CADD

Benign

0.0030

DANN

Benign

0.54

DEOGEN2

Benign

0.011

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.022

LIST_S2

Benign

0.0057

M_CAP

Benign

0.0017

MetaRNN

Benign

0.020

MetaSVM

Benign

-0.93

MutationAssessor

Benign

-0.23

PrimateAI

Benign

0.22

PROVEAN

Benign

1.2

REVEL

Benign

0.026

Sift

Benign

0.19

Sift4G

Benign

0.16

Polyphen

0.0

Vest4

0.068

MutPred

0.29

Gain of phosphorylation at T163 (P = 0.0908);

MVP

0.076

MPC

0.13

ClinPred

0.056

GERP RS

-5.0

Varity_R

0.13

gMVP

0.072

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000082

dbscSNV1_RF

Benign

0.048

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over