Genetic Variant NM_001365405.1:c.441C>G (chr16-66940239-C-G) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001365405.1(CES2):c.441C>G(p.His147Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. H147H) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CES2
NM_001365405.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.66

Publications

1 publications found

Variant links:

Genes affected

CES2 (HGNC:1864): (carboxylesterase 2) 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. The protein encoded by this gene is the major intestinal enzyme and functions in intestine drug clearance. Alternatively spliced transcript variants have been found for this gene.[provided by RefSeq, Oct 2010]

CES2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.885

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001365405.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CES2	NM_001365405.1	MANE Select	c.441C>G	p.His147Gln	missense	Exon 4 of 12	NP_001352334.1	O00748-1
CES2	NM_003869.6		c.441C>G	p.His147Gln	missense	Exon 4 of 12	NP_003860.3
CES2	NM_198061.3		c.441C>G	p.His147Gln	missense	Exon 4 of 12	NP_932327.2	O00748-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CES2	ENST00000317091.10	TSL:1 MANE Select	c.441C>G	p.His147Gln	missense	Exon 4 of 12	ENSP00000317842.5	O00748-1
CES2	ENST00000417689.6	TSL:1	c.441C>G	p.His147Gln	missense	Exon 4 of 12	ENSP00000394452.2	O00748-2
CES2	ENST00000971765.1		c.735C>G	p.His245Gln	missense	Exon 4 of 12	ENSP00000641824.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

250426

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1408852

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

699216

African (AFR)

AF:

0.00

AC:

AN:

31288

American (AMR)

AF:

0.00

AC:

AN:

41432

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24832

East Asian (EAS)

AF:

0.00

AC:

AN:

36682

South Asian (SAS)

AF:

0.00

AC:

AN:

76522

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51348

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5562

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1083360

Other (OTH)

AF:

0.00

AC:

AN:

57826

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000165

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.80

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.21

CADD

Benign

1.0

(source)

DANN

Benign

0.95

DEOGEN2

Uncertain

0.64

Eigen

Benign

-0.84

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.13

LIST_S2

Uncertain

0.95

M_CAP

Uncertain

0.092

MetaRNN

Pathogenic

0.88

MetaSVM

Uncertain

0.34

PhyloP100

-1.7

PrimateAI

Uncertain

0.58

PROVEAN

Pathogenic

-7.7

REVEL

Uncertain

0.50

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0050

Vest4

0.92

MVP

0.15

MPC

0.71

ClinPred

0.95

GERP RS

-11

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over