rs201820739

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_000055.4(BCHE):c.428G>A(p.Gly143Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000328 in 1,614,004 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.00035 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00033 ( 0 hom. )

Consequence

BCHE
NM_000055.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7O:1

Conservation

PhyloP100: 7.80

Variant links:

Genes affected

BCHE (HGNC:983): (butyrylcholinesterase) This gene encodes a cholinesterase enzyme and member of the type-B carboxylesterase/lipase family of proteins. The encoded enzyme exhibits broad substrate specificity and is involved in the detoxification of poisons including organophosphate nerve agents and pesticides, and the metabolism of drugs including cocaine, heroin and aspirin. Humans homozygous for certain mutations in this gene exhibit prolonged apnea after administration of the muscle relaxant succinylcholine. [provided by RefSeq, Jul 2016]

BCHE links:

LINC01322 (HGNC:50528): (long intergenic non-protein coding RNA 1322)

LINC01322 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.94

PP5

Variant 3-165830606-C-T is Pathogenic according to our data. Variant chr3-165830606-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 344097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BCHE	NM_000055.4 link	c.428G>A	p.Gly143Asp	missense_variant	Exon 2 of 4	ENST00000264381.8	NP_000046.1	P06276
BCHE	NR_137636.2 link	n.546G>A		non_coding_transcript_exon_variant	Exon 2 of 5
BCHE	NR_137635.2 link	n.110+6708G>A		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BCHE	ENST00000264381.8 link	c.428G>A	p.Gly143Asp	missense_variant	Exon 2 of 4	1	NM_000055.4	ENSP00000264381.3		P06276

Frequencies

GnomAD3 genomes

AF:

0.000348

AC:

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000544

Gnomad OTH

AF:

0.000958

GnomAD3 exomes

AF:

0.000275

AC:

AN:

250884

Hom.:

AF XY:

0.000310

AC XY:

AN XY:

135628

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00129

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000441

Gnomad OTH exome

AF:

0.000328

GnomAD4 exome

AF:

0.000326

AC:

476

AN:

1461730

Hom.:

Cov.:

AF XY:

0.000319

AC XY:

232

AN XY:

727162

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000179

Gnomad4 ASJ exome

AF:

0.00142

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000375

Gnomad4 OTH exome

AF:

0.000199

GnomAD4 genome

AF:

0.000348

AC:

AN:

152274

Hom.:

Cov.:

AF XY:

0.000242

AC XY:

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.0000722

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.00202

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000544

Gnomad4 OTH

AF:

0.000948

Alfa

AF:

0.000527

Hom.:

Bravo

AF:

0.000378

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000255

AC:

EpiCase

AF:

0.000873

EpiControl

AF:

0.000711

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Deficiency of butyrylcholinesterase

Pathogenic:6Other:1

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpreted as Likely pathogenic and reported on 07-30-2015 by Lab or GTR ID 320494. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Feb 21, 2020

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: BCHE c.428G>A (p.Gly143Asp, legacy names G115D and BCHE*115D) results in a non-conservative amino acid change located in the Carboxylesterase, type B (IPR002018) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00028 in 250884 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in BCHE causing Deficiency of butyrylcholine esterase (0.00028 vs 0.016), allowing no conclusion about variant significance. c.428G>A has been reported in the literature in multiple individuals affected with Deficiency of butyrylcholine esterase resulting in sensitivity to muscle relaxants such as succinylcholine and mivacurium (example, Primo-Parmo_1997, Gatke_2001). It has been subsequently cited by others. These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal butyrylcholineesterase activity in a homozygous individual (example, Primo-Parmo_1997). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=1)/likely pathogenic(n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -

Jan 24, 2018

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BCHE c.428G>A (p.Gly143Asp) missense variant has been reported in at least six studies in which it is found in a total of 15 individuals with butyrylcholinesterase deficiency, including in one in a homozygous state, in 11 in a compound heterozygous state, and in three in a heterozygous state (Primo-Parmo et al. 1997; Gatke et al. 2001; Yen et al. 2003; Gatke et al. 2007; Levano et al. 2008). Control data are unavailable for this variant, which is reported at a frequency of 0.001183 in the Ashkenazi Jewish population of the Genome Aggregation Database. Gatke et al. (2001) reported that individuals with the p.Gly143Asp variant require up to eight hours to reach clinically sufficient neuromuscular function post-dosing of mivicurium, with active isomers present for up to 90 minutes as compared to healthy adults in which isomers were present for 1.5 to 2.3 minutes. The variant occurs in a highly conserved region of BCHE. Functional studies demonstrated that the p.Gly143Asp variant resulted in significantly reduced or absent BCHE activity and only 40% of wild type expression levels (Primo-Parmo et al. 1997; Gatke et al. 2001; Yen et al. 2003). Based on the evidence, the p.Gly143Asp variant is classified as pathogenic for butyrylcholinesterase deficiency, though many individuals who carry pathogenic BCHE variants do not develop clinical complications. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Dec 23, 2016

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 27, 2021

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 16, 2024

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PM3_VSTR,PS3_MOD,PP3,PP4 -

not provided

Pathogenic:1

Sep 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BCHE: PM3:Very Strong, PM2, PS3:Moderate, PP3 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.82

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.59

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.89

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

1.0

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

0.99

M_CAP

Pathogenic

0.42

MetaRNN

Pathogenic

0.94

MetaSVM

Pathogenic

0.92

MutationAssessor

Pathogenic

4.3

PrimateAI

Uncertain

0.72

PROVEAN

Pathogenic

-6.8

REVEL

Pathogenic

0.98

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.97

MVP

1.0

MPC

0.11

ClinPred

0.92

GERP RS

5.8

Varity_R

0.98

gMVP

0.94

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