rs114706984

Positions:

chr3-165830399-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP5BP4BS2

The ENST00000264381.8(BCHE):c.635C>T(p.Ala212Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00377 in 1,613,890 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0025 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0039 ( 11 hom. )

Consequence

BCHE
ENST00000264381.8 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:2

Conservation

PhyloP100: 1.68

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 Likely_benign. Variant got -4 ACMG points.

PP5

Variant 3-165830399-G-A is Pathogenic according to our data. Variant chr3-165830399-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 370854.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=4, Pathogenic=1, Uncertain_significance=2}.

BP4

Computational evidence support a benign effect (MetaRNN=0.029813468). . Strength limited to SUPPORTING due to the PP5.

BS2

High Homozygotes in GnomAdExome4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
BCHE	NM_000055.4 linkuse as main transcript	c.635C>T	p.Ala212Val	missense_variant	2/4	ENST00000264381.8	NP_000046.1
BCHE	NR_137636.2 linkuse as main transcript	n.753C>T		non_coding_transcript_exon_variant	2/5
BCHE	NR_137635.2 linkuse as main transcript	n.110+6915C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BCHE	ENST00000264381.8 linkuse as main transcript	c.635C>T	p.Ala212Val	missense_variant	2/4	1	NM_000055.4	ENSP00000264381	P1
LINC01322	ENST00000651449.1 linkuse as main transcript	n.1008-15493G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.00248

AC:

377

AN:

152084

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00116

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00131

Gnomad ASJ

AF:

0.00433

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00419

Gnomad OTH

AF:

0.00192

GnomAD3 exomes

AF:

0.00211

AC:

527

AN:

250210

Hom.:

AF XY:

0.00208

AC XY:

281

AN XY:

135374

show subpopulations

Gnomad AFR exome

AF:

0.00138

Gnomad AMR exome

AF:

0.00133

Gnomad ASJ exome

AF:

0.00339

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000327

Gnomad FIN exome

AF:

0.000185

Gnomad NFE exome

AF:

0.00354

Gnomad OTH exome

AF:

0.00181

GnomAD4 exome

AF:

0.00391

AC:

5714

AN:

1461688

Hom.:

Cov.:

AF XY:

0.00370

AC XY:

2690

AN XY:

727118

show subpopulations

Gnomad4 AFR exome

AF:

0.000598

Gnomad4 AMR exome

AF:

0.00112

Gnomad4 ASJ exome

AF:

0.00310

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000267

Gnomad4 FIN exome

AF:

0.000281

Gnomad4 NFE exome

AF:

0.00482

Gnomad4 OTH exome

AF:

0.00278

GnomAD4 genome

AF:

0.00247

AC:

376

AN:

152202

Hom.:

Cov.:

AF XY:

0.00214

AC XY:

159

AN XY:

74406

show subpopulations

Gnomad4 AFR

AF:

0.00113

Gnomad4 AMR

AF:

0.00131

Gnomad4 ASJ

AF:

0.00433

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.000283

Gnomad4 NFE

AF:

0.00419

Gnomad4 OTH

AF:

0.00190

Alfa

AF:

0.00384

Hom.:

Bravo

AF:

0.00263

TwinsUK

AF:

0.00593

AC:

ALSPAC

AF:

0.00441

AC:

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00419

AC:

ExAC

AF:

0.00186

AC:

226

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00267

EpiControl

AF:

0.00362

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Deficiency of butyrylcholinesterase

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Sep 07, 2017	The BCHE c.635C>T (p.Ala212Val) missense variant, also referred to as p.Ala184Val, has been identified in at least four studies and seven individuals with low BChE activity, including in one in a homozygous state, in three in a compound heterozygous state, and in three in a heterozygous state (Greenberg et al. 1995; Levano et al. 2005; Mikami et al. 2008; Jasiecki et al. 2016). Two of the compound heterozygous individuals were found to have prolonged duration of succinylcholine action during routine anesthetic administration (Greenberg et al. 1995; Levano et al. 2005). The p.Ala212Val variant is reported at a frequency of 0.00419 in the European-American population of the Exome Sequencing Project. Based on the evidence, the p.Ala212Val is classified as likely pathogenic for butyrylcholinesterase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Apr 28, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Oct 10, 2024	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as likely pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0106 - This gene is known to be associated with autosomal recessive disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from alanine to valine (exon 2). (N) 0251 - Variant is heterozygous. (N) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (593 heterozygotes, 1 homozygote). (P) 0503 - Missense variant consistently predicted to be tolerated or not conserved in mammals with a minor amino acid change. (B) 0600 - Variant is located in an annotated domain or motif (COesterase domain; NCBI, PDB). (N) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0801 - Strong previous evidence of pathogenicity in several unrelated individuals, both compound heterozygote (PMID:27109752, PMID:7618741) and homozygote (PMID:18300943). (P) 0905 - No segregation evidence has been identified for this variant. (N) 1002 - Moderate functional evidence supporting abnormal protein function, where mutant protein showed 70% of normal protein function (PMID:25448037). (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -

not provided

Pathogenic:1Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 23, 2023	The BCHE c.635C>T; p.Ala212Val variant, also published as Ala184Val, is reported in the literature as occurring in the homozygous state, compound heterozygous state, and heterozygous state, with at least two of the compound heterozygous individuals experiencing prolonged duration of succinylcholine action during routine anesthetic administration and reduced BChE activity (Greenberg 1995, Levano 2005, Mikami 2008). The variant is also listed in the ClinVar database (Variation ID: 370854), and is found in the general population with an overall allele frequency of 0.2% (595/281,610 alleles, including 1 homozygote) in the Genome Aggregation Database (v2.1.1). Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.365). Based on available information, the p.Ala212Val variant is classified as likely pathogenic. References: Greenberg CP et al. Prolonged response to succinylcholine: a new variant of plasma cholinesterase that is identified as normal by traditional phenotyping methods. Anesth Analg. 1995 Aug;81(2):419-21. PMID: 7618741. Levano S et al. Genotyping the butyrylcholinesterase in patients with prolonged neuromuscular block after succinylcholine. Anesthesiology. 2005 Mar;102(3):531-5. PMID: 15731589. Mikami LR et al. Five new naturally occurring mutations of the BCHE gene and frequencies of 12 butyrylcholinesterase alleles in a Brazilian population. Pharmacogenet Genomics. 2008 Mar;18(3):213-8. PMID: 18300943. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 25, 2022	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31589614, 18300943, 22750491, 20589221, 15731589, 7618741, 27109752) -

See cases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Dec 02, 2020

ACMG classification criteria: PS3, PS4, PM3, BP4 -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Jul 31, 2024

Variant summary: BCHE c.635C>T (p.Ala212Val; aka. 551C>T, A184V or SC variant) results in a non-conservative amino acid change located in the Carboxylesterase, type B domain (IPR002018) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0021 in 250210 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is lower than the estimated maximum expected for a pathogenic variant in BCHE causing Deficiency of Butyrylcholine Esterase (0.0021 vs 0.016), allowing no conclusion about variant significance. c.635C>T has been reported in the literature in at least two compound heterozygous individuals with a prolonged response to Succinylcholine (Greenberg_1995, Levano_2005), a homozygous blood donor whose enzyme activity was not specified (Mikami_2008) and as a compound heterozygous genotype in a healthy Polish individual with normal Butrylcholine esterase activity, but abnormal Dibucaine number (Jasiecki_2016). At least one publication reports reduced plasma cholinesterase activity in compound heterozygous individual (Greenberg_1995), however this result doesn't allow conclusions for the individual effect of the variant. The following publications have been ascertained in the context of this evaluation (PMID: 7618741, 27109752, 15731589, 18300943, 20589221). ClinVar contains an entry for this variant (Variation ID: 370854). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.20

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.58

Eigen

Benign

-0.065

Eigen_PC

Benign

0.012

FATHMM_MKL

Benign

0.48

LIST_S2

Benign

0.84

M_CAP

Benign

0.018

MetaRNN

Benign

0.030

MetaSVM

Benign

-0.74

MutationAssessor

Uncertain

2.6

MutationTaster

Benign

1.0

D;D

PrimateAI

Benign

0.42

PROVEAN

Benign

-2.0

REVEL

Uncertain

0.36

Sift

Benign

0.31

Sift4G

Benign

0.48

Polyphen

0.35

Vest4

0.22

MVP

0.92

MPC

0.014

ClinPred

0.86

GERP RS

4.8

Varity_R

0.49

gMVP

0.54

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