rs201820739

Positions:

• chr3-165830606-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7 O:1
• Conservation: PhyloP100: 7.80

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 (HGNC:):

ACMG classification

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/exons	MANE	Protein	UniProt
BCHE	NM_000055.4	c.428G>A	p.Gly143Asp	missense_variant	2/4	ENST00000264381.8	NP_000046.1
BCHE	NR_137636.2	n.546G>A		non_coding_transcript_exon_variant	2/5
BCHE	NR_137635.2	n.110+6708G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BCHE	ENST00000264381.8	c.428G>A	p.Gly143Asp	missense_variant	2/4	1	NM_000055.4	ENSP00000264381.3

Frequencies

GnomAD3 genomes AF: 0.000348 AC: 53 AN: 152156 Hom.: 0 Cov.: 32

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: 69 AN: 250884 Hom.: 0 AF XY: 0.000310 AC XY: 42 AN XY: 135628

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.: 0 Cov.: 31 AF XY: 0.000319 AC XY: 232 AN XY: 727162

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: 53 AN: 152274 Hom.: 0 Cov.: 32 AF XY: 0.000242 AC XY: 18 AN XY: 74464

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.: 0

Bravo AF: 0.000378

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000255 AC: 31

EpiCase AF: 0.000873

EpiControl AF: 0.000711

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Deficiency of butyrylcholinesterase Pathogenic:6 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jul 16, 2024	Criteria applied: PM3_VSTR,PS3_MOD,PP3,PP4 -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 21, 2020	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 27, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 24, 2018	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. -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Dec 23, 2016	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Sep 01, 2023

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	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.42	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Pathogenic	4.3	H
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-6.8	D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.97
MVP		1.0
MPC		0.11
ClinPred		0.92	D
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

Other links and lift over

dbSNP: rs201820739; hg19: chr3-165548394;