16-55823658-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001025195.2(CES1):c.431G>A(p.Gly144Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.01 in 151,662 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as drug response (★★★).

Frequency

Genomes: 𝑓 0.010 ( 0 hom., cov: 39)

Exomes 𝑓: 0.012 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CES1
NM_001025195.2 missense

Scores

Clinical Significance

drug response reviewed by expert panel P:1B:1O:2

Conservation

PhyloP100: 0.892

Publications

140 publications found

Variant links:

COSMIC-nc: COSV107467882

Genes affected

CES1 (HGNC:1863): (carboxylesterase 1) This gene encodes a member of the carboxylesterase large family. The family members are responsible for the hydrolysis or transesterification of various xenobiotics, such as cocaine and heroin, and endogenous substrates with ester, thioester, or amide bonds. They may participate in fatty acyl and cholesterol ester metabolism, and may play a role in the blood-brain barrier system. This enzyme is the major liver enzyme and functions in liver drug clearance. Mutations of this gene cause carboxylesterase 1 deficiency. Three transcript variants encoding three different isoforms have been found for this gene. [provided by RefSeq, Jun 2010]

CES1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.03447321).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CES1	NM_001025195.2 link	c.431G>A	p.Gly144Glu	missense_variant	Exon 4 of 14	ENST00000360526.8	NP_001020366.1	P23141-2
CES1	NM_001025194.2 link	c.428G>A	p.Gly143Glu	missense_variant	Exon 4 of 14		NP_001020365.1	P23141-1
CES1	NM_001266.5 link	c.428G>A	p.Gly143Glu	missense_variant	Exon 4 of 14		NP_001257.4	P23141-3
CES1	XM_005255774.3 link	c.431G>A	p.Gly144Glu	missense_variant	Exon 4 of 14		XP_005255831.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CES1	ENST00000360526.8 link	c.431G>A	p.Gly144Glu	missense_variant	Exon 4 of 14	1	NM_001025195.2	ENSP00000353720.4		P23141-2

Frequencies

GnomAD3 genomes

AF:

0.0100

AC:

1519

AN:

151544

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00237

Gnomad AMI

AF:

0.00330

Gnomad AMR

AF:

0.0106

Gnomad ASJ

AF:

0.0235

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00685

Gnomad FIN

AF:

0.0108

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0148

Gnomad OTH

AF:

0.0101

GnomAD2 exomes

AF:

0.0109

AC:

2725

AN:

249588

AF XY:

0.0112

show subpopulations

Gnomad AFR exome

AF:

0.00179

Gnomad AMR exome

AF:

0.00693

Gnomad ASJ exome

AF:

0.0260

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.0114

Gnomad NFE exome

AF:

0.0148

Gnomad OTH exome

AF:

0.0158

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0119

AC:

17324

AN:

1450200

Hom.:

Cov.:

AF XY:

0.0120

AC XY:

8645

AN XY:

721462

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00248

AC:

AN:

33448

American (AMR)

AF:

0.00749

AC:

334

AN:

44588

Ashkenazi Jewish (ASJ)

AF:

0.0257

AC:

663

AN:

25818

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39698

South Asian (SAS)

AF:

0.00658

AC:

566

AN:

86044

European-Finnish (FIN)

AF:

0.0127

AC:

674

AN:

52988

Middle Eastern (MID)

AF:

0.0110

AC:

AN:

5732

European-Non Finnish (NFE)

AF:

0.0129

AC:

14171

AN:

1101962

Other (OTH)

AF:

0.0128

AC:

768

AN:

59922

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.266

Heterozygous variant carriers

1816

3632

5448

7264

9080

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

508

1016

1524

2032

2540

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0100

AC:

1519

AN:

151662

Hom.:

Cov.:

AF XY:

0.00930

AC XY:

690

AN XY:

74154

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00236

AC:

AN:

41518

American (AMR)

AF:

0.0106

AC:

161

AN:

15240

Ashkenazi Jewish (ASJ)

AF:

0.0235

AC:

AN:

3440

East Asian (EAS)

AF:

0.000193

AC:

AN:

5182

South Asian (SAS)

AF:

0.00686

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.0108

AC:

114

AN:

10566

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0148

AC:

1002

AN:

67602

Other (OTH)

AF:

0.0100

AC:

AN:

2098

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.293

Heterozygous variant carriers

104

208

313

417

521

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0134

Hom.:

ESP6500AA

AF:

0.00114

AC:

ESP6500EA

AF:

0.00942

AC:

ExAC

AF:

0.0144

AC:

1747

ClinVar

Significance: drug response

Submissions summary: Pathogenic:1Benign:1Other:2

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Benign:1

May 15, 2018

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Nov 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CES1: PM1, PS4:Moderate, PP4, PS3:Supporting -

clopidogrel response - Efficacy

Other:1

Mar 24, 2021

PharmGKB

Significance:drug response

Review Status:reviewed by expert panel

Collection Method:curation

PharmGKB Level of Evidence 2B: Variants in Level 2B clinical annotations are not in PharmGKB’s Tier 1 VIPs. These clinical annotations describe variant-drug combinations with a moderate level of evidence supporting the association. For example, the association may be found in multiple cohorts, but there may be a minority of studies that do not support the majority assertion. Level 2B clinical annotations must be supported by at least two independent publications. Drug-variant association: Efficacy

clopidogrel response - Metabolism/PK

Other:1

Mar 24, 2021

PharmGKB

Significance:drug response

Review Status:reviewed by expert panel

Collection Method:curation

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.85

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.21

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.59

.;.;D

Eigen

Benign

0.15

Eigen_PC

Benign

-0.15

FATHMM_MKL

Benign

0.72

LIST_S2

Uncertain

0.95

D;D;D

MetaRNN

Benign

0.034

T;T;T

MetaSVM

Benign

-0.88

MutationAssessor

Pathogenic

3.2

.;M;M

PhyloP100

0.89

PrimateAI

Benign

0.40

PROVEAN

Pathogenic

-6.6

D;D;D

REVEL

Benign

0.24

Sift

Uncertain

0.0010

D;D;D

Sift4G

Uncertain

0.0020

D;D;D

Polyphen

1.0

D;.;D

Vest4

0.29

MPC

0.23

ClinPred

0.059

GERP RS

1.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.94

gMVP

0.73

Mutation Taster

=66/34

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over