16-55811002-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001025195.2(CES1):​c.1095G>A​(p.Met365Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,454,560 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 34)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

CES1
NM_001025195.2 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.77
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.20641002).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CES1NM_001025195.2 linkc.1095G>A p.Met365Ile missense_variant Exon 10 of 14 ENST00000360526.8 NP_001020366.1 P23141-2
CES1NM_001025194.2 linkc.1092G>A p.Met364Ile missense_variant Exon 10 of 14 NP_001020365.1 P23141-1
CES1NM_001266.5 linkc.1089G>A p.Met363Ile missense_variant Exon 10 of 14 NP_001257.4 P23141-3
CES1XM_005255774.3 linkc.1092G>A p.Met364Ile missense_variant Exon 10 of 14 XP_005255831.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CES1ENST00000360526.8 linkc.1095G>A p.Met365Ile missense_variant Exon 10 of 14 1 NM_001025195.2 ENSP00000353720.4 P23141-2

Frequencies

GnomAD3 genomes
Cov.:
34
GnomAD3 exomes
AF:
0.00000406
AC:
1
AN:
246188
Hom.:
0
AF XY:
0.00000752
AC XY:
1
AN XY:
133026
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000547
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1454560
Hom.:
0
Cov.:
33
AF XY:
0.00000138
AC XY:
1
AN XY:
723924
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.0000384
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
34

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Sep 26, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1092G>A (p.M364I) alteration is located in exon 10 (coding exon 10) of the CES1 gene. This alteration results from a G to A substitution at nucleotide position 1092, causing the methionine (M) at amino acid position 364 to be replaced by an isoleucine (I). 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
Uncertain
0.36
BayesDel_addAF
Benign
-0.22
T
BayesDel_noAF
Benign
-0.39
CADD
Benign
17
DANN
Benign
0.49
DEOGEN2
Benign
0.20
.;.;T
Eigen
Benign
-0.58
Eigen_PC
Benign
-0.51
FATHMM_MKL
Benign
0.37
N
LIST_S2
Benign
0.20
T;T;T
M_CAP
Benign
0.022
T
MetaRNN
Benign
0.21
T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.91
.;.;L
PrimateAI
Benign
0.44
T
PROVEAN
Benign
-2.3
N;N;N
REVEL
Benign
0.059
Sift
Benign
0.36
T;T;T
Sift4G
Benign
0.34
T;T;T
Polyphen
0.0020
B;.;B
Vest4
0.41
MutPred
0.39
.;.;Gain of catalytic residue at M364 (P = 0.037);
MVP
0.38
MPC
0.029
ClinPred
0.14
T
GERP RS
3.6
Varity_R
0.45
gMVP
0.39

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.

Other links and lift over

dbSNP: rs747321428; hg19: chr16-55844914; COSMIC: COSV62086992; COSMIC: COSV62086992; API