16-55852977-T-C

Position:

chr16-55852977-T-C

Variant summary

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

The NM_001143685.2(CES5A):c.1177A>G(p.Lys393Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,136 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CES5A
NM_001143685.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.535

Variant links:

Genes affected

CES5A (HGNC:26459): (carboxylesterase 5A) 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 also participate in fatty acyl and cholesterol ester metabolism, and may play a role in the blood-brain barrier system. This gene, also called CES5, is predominantly expressed in peripheral tissues, including brain, kidney, lung and testis. It encodes a secreted enzyme. Because of high levels in the urine of male domestic cats, this enzyme is also called cauxin (carboxylesterase-like urinary excreted protein). The enzyme functions in regulating the production of a pheromone precursor and may contribute to lipid and cholesterol transfer processes within male reproductive fluids. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jun 2010]

CES5A links:

CES5A (HGNC:):

CES5A links:

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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=0.09883976).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CES5A	NM_001143685.2 linkuse as main transcript	c.1177A>G	p.Lys393Glu	missense_variant	10/13	ENST00000290567.14	NP_001137157.1	Q6NT32-1
CES5A	NM_001190158.1 linkuse as main transcript	c.1264A>G	p.Lys422Glu	missense_variant	11/14		NP_001177087.1	Q6NT32-4
CES5A	NM_145024.3 linkuse as main transcript	c.1177A>G	p.Lys393Glu	missense_variant	10/12		NP_659461.1	Q6NT32-2V9HWK3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CES5A	ENST00000290567.14 linkuse as main transcript	c.1177A>G	p.Lys393Glu	missense_variant	10/13	1	NM_001143685.2	ENSP00000290567.9		Q6NT32-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

6.84e-7

AC:

AN:

1461862

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727232

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

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

AF:

0.00000657

AC:

AN:

152136

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74306

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 30, 2024

The c.1264A>G (p.K422E) alteration is located in exon 11 (coding exon 11) of the CES5A gene. This alteration results from a A to G substitution at nucleotide position 1264, causing the lysine (K) at amino acid position 422 to be replaced by a glutamic acid (E). 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

Benign

0.12

BayesDel_addAF

Benign

-0.098

BayesDel_noAF

Benign

-0.38

CADD

Benign

9.2

DANN

Uncertain

0.99

DEOGEN2

Benign

0.040

.;.;.;T;T;T

Eigen

Benign

-0.69

Eigen_PC

Benign

-0.65

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.62

T;T;T;T;T;T

M_CAP

Benign

0.030

MetaRNN

Benign

0.099

T;T;T;T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.015

.;N;.;N;.;.

MutationTaster

Benign

1.0

N;N;N;N;N

PrimateAI

Benign

0.43

PROVEAN

Benign

-1.0

N;N;N;N;N;.

REVEL

Benign

0.067

Sift

Benign

0.062

T;D;T;D;D;.

Sift4G

Benign

0.44

T;T;T;T;T;T

Polyphen

0.012, 0.12

.;B;.;B;.;.

Vest4

0.18

MutPred

0.40

.;Loss of ubiquitination at K393 (P = 0.0155);.;Loss of ubiquitination at K393 (P = 0.0155);.;.;

MVP

0.10

MPC

0.050

ClinPred

0.24

GERP RS

4.3

Varity_R

0.25

gMVP

0.44

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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