Genetic Variant CES1:p.Ser12Ala (chr16-55833022-A-C) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001025195.2(CES1):c.34T>G(p.Ser12Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00232 in 1,398,326 control chromosomes in the GnomAD database, including 1,061 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.037 ( 273 hom., cov: 31)

Exomes 𝑓: 0.0023 ( 1061 hom. )

Failed GnomAD Quality Control

Consequence

CES1
NM_001025195.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -4.62

Publications

22 publications found

Variant links:

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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.003278941).

BS2

High Homozygotes in GnomAdExome4 at 1061 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
CES1	NM_001025195.2 link	c.34T>G	p.Ser12Ala	missense_variant	Exon 1 of 14	ENST00000360526.8	NP_001020366.1
CES1	NM_001025194.2 link	c.34T>G	p.Ser12Ala	missense_variant	Exon 1 of 14		NP_001020365.1
CES1	NM_001266.5 link	c.34T>G	p.Ser12Ala	missense_variant	Exon 1 of 14		NP_001257.4
CES1	XM_005255774.3 link	c.34T>G	p.Ser12Ala	missense_variant	Exon 1 of 14		XP_005255831.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CES1	ENST00000360526.8 link	c.34T>G	p.Ser12Ala	missense_variant	Exon 1 of 14	1	NM_001025195.2	ENSP00000353720.4

Frequencies

GnomAD3 genomes

AF:

0.0374

AC:

4664

AN:

124722

Hom.:

273

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0452

Gnomad AMI

AF:

0.00463

Gnomad AMR

AF:

0.0313

Gnomad ASJ

AF:

0.0318

Gnomad EAS

AF:

0.0424

Gnomad SAS

AF:

0.0487

Gnomad FIN

AF:

0.0347

Gnomad MID

AF:

0.108

Gnomad NFE

AF:

0.0339

Gnomad OTH

AF:

0.0386

GnomAD2 exomes

AF:

0.00649

AC:

1573

AN:

242522

AF XY:

0.00680

show subpopulations

Gnomad AFR exome

AF:

0.0137

Gnomad AMR exome

AF:

0.00417

Gnomad ASJ exome

AF:

0.00194

Gnomad EAS exome

AF:

0.0167

Gnomad FIN exome

AF:

0.000524

Gnomad NFE exome

AF:

0.00365

Gnomad OTH exome

AF:

0.00646

GnomAD4 exome

AF:

0.00232

AC:

3251

AN:

1398326

Hom.:

1061

Cov.:

AF XY:

0.00281

AC XY:

1953

AN XY:

695638

show subpopulations

African (AFR)

AF:

0.00892

AC:

284

AN:

31840

American (AMR)

AF:

0.00228

AC:

100

AN:

43912

Ashkenazi Jewish (ASJ)

AF:

0.000915

AC:

AN:

25126

East Asian (EAS)

AF:

0.00413

AC:

149

AN:

36048

South Asian (SAS)

AF:

0.0136

AC:

1118

AN:

82476

European-Finnish (FIN)

AF:

0.00541

AC:

276

AN:

51048

Middle Eastern (MID)

AF:

0.00341

AC:

AN:

5280

European-Non Finnish (NFE)

AF:

0.00105

AC:

1122

AN:

1065068

Other (OTH)

AF:

0.00280

AC:

161

AN:

57528

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.444

Heterozygous variant carriers

115

154

192

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0374

AC:

4665

AN:

124838

Hom.:

273

Cov.:

AF XY:

0.0365

AC XY:

2225

AN XY:

60886

show subpopulations

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

African (AFR)

AF:

0.0452

AC:

1534

AN:

33924

American (AMR)

AF:

0.0312

AC:

405

AN:

12990

Ashkenazi Jewish (ASJ)

AF:

0.0318

AC:

AN:

2926

East Asian (EAS)

AF:

0.0425

AC:

160

AN:

3762

South Asian (SAS)

AF:

0.0474

AC:

177

AN:

3738

European-Finnish (FIN)

AF:

0.0347

AC:

302

AN:

8706

Middle Eastern (MID)

AF:

0.108

AC:

AN:

204

European-Non Finnish (NFE)

AF:

0.0339

AC:

1902

AN:

56084

Other (OTH)

AF:

0.0402

AC:

AN:

1640

⚠️ 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: 0.282

Heterozygous variant carriers

442

884

1325

1767

2209

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

168

224

280

<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:

0.0608

Hom.:

444

ESP6500AA

AF:

0.00809

AC:

ESP6500EA

AF:

0.00191

AC:

ExAC

AF:

0.00273

AC:

322

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.054

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.71

CADD

Benign

0.0010

(source)

DANN

Benign

0.33

DEOGEN2

Benign

0.0

.;.;T

Eigen

Benign

-2.2

Eigen_PC

Benign

-2.2

LIST_S2

Benign

0.037

T;T;T

MetaRNN

Benign

0.0033

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.20

N;N;N

PhyloP100

-4.6

PrimateAI

Benign

0.39

PROVEAN

Benign

0.42

N;N;N

Sift

Benign

0.95

T;T;T

Sift4G

Benign

1.0

T;T;T

Vest4

0.030

ClinPred

0.0041

GERP RS

-7.6

PromoterAI

0.12

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.045

gMVP

0.17

Mutation Taster

=98/2

polymorphism (auto)

(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

Computational scores

Splicing

Publications

Other links and lift over