16-55823658-C-T

Variant summary

Our verdict is Likely benign. Variant got -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
• Clinical Significance: drug response reviewed by expert panel P:1 B:1 O:2
• Conservation: PhyloP100: 0.892

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]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03447321).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CES1	NM_001025195.2	c.431G>A	p.Gly144Glu	missense_variant	4/14	ENST00000360526.8
CES1	NM_001025194.2	c.428G>A	p.Gly143Glu	missense_variant	4/14
CES1	NM_001266.5	c.428G>A	p.Gly143Glu	missense_variant	4/14
CES1	XM_005255774.3	c.431G>A	p.Gly144Glu	missense_variant	4/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CES1	ENST00000360526.8	c.431G>A	p.Gly144Glu	missense_variant	4/14	1	NM_001025195.2	P4

Frequencies

GnomAD3 genomes AF: 0.0100 AC: 1519 AN: 151544 Hom.: 0 Cov.: 39

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

GnomAD3 exomes AF: 0.0109 AC: 2725 AN: 249588 Hom.: 0 AF XY: 0.0112 AC XY: 1505 AN XY: 134858

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 SAS exome AF: 0.00613

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.: 0 Cov.: 35 AF XY: 0.0120 AC XY: 8645 AN XY: 721462

Gnomad4 AFR exome AF: 0.00248

Gnomad4 AMR exome AF: 0.00749

Gnomad4 ASJ exome AF: 0.0257

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00658

Gnomad4 FIN exome AF: 0.0127

Gnomad4 NFE exome AF: 0.0129

Gnomad4 OTH exome AF: 0.0128

GnomAD4 genome AF: 0.0100 AC: 1519 AN: 151662 Hom.: 0 Cov.: 39 AF XY: 0.00930 AC XY: 690 AN XY: 74154

Gnomad4 AFR AF: 0.00236

Gnomad4 AMR AF: 0.0106

Gnomad4 ASJ AF: 0.0235

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00686

Gnomad4 FIN AF: 0.0108

Gnomad4 NFE AF: 0.0148

Gnomad4 OTH AF: 0.0100

Alfa AF: 0.0141 Hom.: 0

ESP6500AA AF: 0.00114 AC: 5

ESP6500EA AF: 0.00942 AC: 81

ExAC AF: 0.0144 AC: 1747

ClinVar

Significance: drug response

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

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:1 Benign:1

Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2022	CES1: PM1, PS4:Moderate, PP4, PS3:Supporting -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 15, 2018	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. -

clopidogrel response - Efficacy Other:1

drug response, reviewed by expert panel

curation

PharmGKB

Mar 24, 2021

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

drug response, reviewed by expert panel

curation

PharmGKB

Mar 24, 2021

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: Metabolism/PK

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.21
Cadd	Benign	21
Dann	Uncertain	0.99
Eigen	Benign	0.15
Eigen_PC	Benign	-0.15
FATHMM_MKL	Benign	0.72	D
LIST_S2	Uncertain	0.95	D;D;D
MetaRNN	Benign	0.034	T;T;T
MetaSVM	Benign	-0.88	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.40	T
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	T
GERP RS		1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.94
gMVP		0.73

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

Other links and lift over

dbSNP: rs71647871; hg19: chr16-55857570;