10-94683950-A-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_000772.3(CYP2C18):c.131A>T(p.Gln44Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000048 in 1,457,990 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

CYP2C18
NM_000772.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.63

Publications

1 publications found

Variant links:

COSMIC-nc: COSV53674670

Genes affected

CYP2C18 (HGNC:2620): (cytochrome P450 family 2 subfamily C member 18) 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 but its specific substrate has not yet been determined. The gene is located within a cluster of cytochrome P450 genes on chromosome 10q24. An additional gene, CYP2C17, was once thought to exist; however, CYP2C17 is now considered an artefact based on a chimera of CYP2C18 and CYP2C19. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

CYP2C18 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.883

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP2C18	NM_000772.3 link	c.131A>T	p.Gln44Leu	missense_variant	Exon 1 of 9	ENST00000285979.11	NP_000763.1	P33260-1Q7Z348
CYP2C18	NM_001128925.2 link	c.131A>T	p.Gln44Leu	missense_variant	Exon 1 of 8		NP_001122397.1	P33260-2Q7Z348

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP2C18	ENST00000285979.11 link	c.131A>T	p.Gln44Leu	missense_variant	Exon 1 of 9	1	NM_000772.3	ENSP00000285979.6		P33260-1
CYP2C18	ENST00000339022.6 link	c.131A>T	p.Gln44Leu	missense_variant	Exon 1 of 8	1		ENSP00000341293.5		P33260-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000282

AC:

AN:

248256

AF XY:

0.0000373

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000383

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000480

AC:

AN:

1457990

Hom.:

Cov.:

AF XY:

0.00000552

AC XY:

AN XY:

725048

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33428

American (AMR)

AF:

0.00

AC:

AN:

44162

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26100

East Asian (EAS)

AF:

0.000151

AC:

AN:

39616

South Asian (SAS)

AF:

0.00

AC:

AN:

85066

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53372

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5718

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1110270

Other (OTH)

AF:

0.0000166

AC:

AN:

60258

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 22, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.131A>T (p.Q44L) alteration is located in exon 1 (coding exon 1) of the CYP2C18 gene. This alteration results from a A to T substitution at nucleotide position 131, causing the glutamine (Q) at amino acid position 44 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.27

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.25

T;.

Eigen

Benign

-0.078

Eigen_PC

Benign

-0.086

FATHMM_MKL

Benign

0.40

LIST_S2

Benign

0.78

T;T

M_CAP

Benign

0.011

MetaRNN

Pathogenic

0.88

D;D

MetaSVM

Benign

-0.76

MutationAssessor

Uncertain

2.1

M;M

PhyloP100

4.6

PROVEAN

Pathogenic

-5.6

D;D

REVEL

Benign

0.25

Sift

Uncertain

0.021

D;D

Sift4G

Uncertain

0.034

D;T

Polyphen

0.28

B;.

Vest4

0.60

MutPred

0.73

Gain of catalytic residue at Q44 (P = 0.0649);Gain of catalytic residue at Q44 (P = 0.0649);

MVP

0.70

MPC

0.018

ClinPred

0.72

GERP RS

2.9

PromoterAI

0.047

Neutral

(source)

Varity_R

0.26

gMVP

0.64

Mutation Taster

=87/13

polymorphism

(source)

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

Publications

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10-94683950-A-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over