16-55810997-T-C

Variant names:

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_001025195.2(CES1):c.1100A>G(p.Tyr367Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000647 in 1,602,090 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00073 ( 0 hom., cov: 34)

Exomes 𝑓: 0.00064 ( 0 hom. )

Consequence

CES1
NM_001025195.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: -0.275

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.067707956).

BP6

Variant 16-55810997-T-C is Benign according to our data. Variant chr16-55810997-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 3143217.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}. Variant chr16-55810997-T-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000639 (933/1460408) while in subpopulation MID AF= 0.0232 (133/5740). AF 95% confidence interval is 0.02. There are 0 homozygotes in gnomad4_exome. There are 497 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CES1	NM_001025195.2 link	c.1100A>G	p.Tyr367Cys	missense_variant	Exon 10 of 14	ENST00000360526.8	NP_001020366.1	P23141-2
CES1	NM_001025194.2 link	c.1097A>G	p.Tyr366Cys	missense_variant	Exon 10 of 14		NP_001020365.1	P23141-1
CES1	NM_001266.5 link	c.1094A>G	p.Tyr365Cys	missense_variant	Exon 10 of 14		NP_001257.4	P23141-3
CES1	XM_005255774.3 link	c.1097A>G	p.Tyr366Cys	missense_variant	Exon 10 of 14		XP_005255831.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CES1	ENST00000360526.8 link	c.1100A>G	p.Tyr367Cys	missense_variant	Exon 10 of 14	1	NM_001025195.2	ENSP00000353720.4		P23141-2

Frequencies

GnomAD3 genomes

AF:

0.000735

AC:

104

AN:

141570

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000189

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000955

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000196

Gnomad SAS

AF:

0.00176

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0197

Gnomad NFE

AF:

0.000993

Gnomad OTH

AF:

0.00212

GnomAD3 exomes

AF:

0.000804

AC:

201

AN:

249928

Hom.:

AF XY:

0.000822

AC XY:

111

AN XY:

135052

show subpopulations

Gnomad AFR exome

AF:

0.0000628

Gnomad AMR exome

AF:

0.00160

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00141

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000699

Gnomad OTH exome

AF:

0.00377

GnomAD4 exome

AF:

0.000639

AC:

933

AN:

1460408

Hom.:

Cov.:

AF XY:

0.000684

AC XY:

497

AN XY:

726524

show subpopulations

Gnomad4 AFR exome

AF:

0.000239

Gnomad4 AMR exome

AF:

0.00172

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00107

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000472

Gnomad4 OTH exome

AF:

0.00159

GnomAD4 genome

AF:

0.000734

AC:

104

AN:

141682

Hom.:

Cov.:

AF XY:

0.000715

AC XY:

AN XY:

68536

show subpopulations

Gnomad4 AFR

AF:

0.000188

Gnomad4 AMR

AF:

0.000953

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000197

Gnomad4 SAS

AF:

0.00176

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000993

Gnomad4 OTH

AF:

0.00210

Alfa

AF:

0.00104

Hom.:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.000840

AC:

102

Asia WGS

AF:

0.00375

AC:

AN:

3478

EpiCase

AF:

0.00115

EpiControl

AF:

0.00143

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 20, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1097A>G (p.Y366C) alteration is located in exon 10 (coding exon 10) of the CES1 gene. This alteration results from a A to G substitution at nucleotide position 1097, causing the tyrosine (Y) at amino acid position 366 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Benign:1

Jun 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CES1: BP4 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.35

CADD

Benign

DANN

Benign

0.56

DEOGEN2

Uncertain

0.44

.;.;T

Eigen

Benign

-0.91

Eigen_PC

Benign

-0.97

FATHMM_MKL

Benign

0.046

LIST_S2

Benign

0.31

T;T;T

M_CAP

Benign

0.061

MetaRNN

Benign

0.068

T;T;T

MetaSVM

Benign

-0.79

MutationAssessor

Uncertain

2.2

.;.;M

PrimateAI

Benign

0.43

PROVEAN

Pathogenic

-4.9

D;D;D

REVEL

Benign

0.18

Sift

Benign

0.091

T;T;T

Sift4G

Benign

0.14

T;T;T

Polyphen

0.073

B;.;B

Vest4

0.62

MVP

0.35

MPC

0.19

ClinPred

0.029

GERP RS

0.63

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.41

gMVP

0.59

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

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