rs114706984

chr3-165830399-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP5 BP4

The NM_000055.4(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 NM_000055.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:2
• Conservation: PhyloP100: 1.68

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]

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

ACMG classification

Verdict is Uncertain_significance. Variant got 0 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: {Uncertain_significance=2, Likely_pathogenic=4, Pathogenic=1}.
• BP4: Computational evidence support a benign effect (MetaRNN=0.029813468).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.00248 AC: 377 AN: 152084 Hom.: 0 Cov.: 32

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.: 1 AF XY: 0.00208 AC XY: 281 AN XY: 135374

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.: 11 Cov.: 31 AF XY: 0.00370 AC XY: 2690 AN XY: 727118

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.: 0 Cov.: 32 AF XY: 0.00214 AC XY: 159 AN XY: 74406

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.: 2

Bravo AF: 0.00263

TwinsUK AF: 0.00593 AC: 22

ALSPAC AF: 0.00441 AC: 17

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00419 AC: 36

ExAC AF: 0.00186 AC: 226

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00267

EpiControl AF: 0.00362

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:2

Revision: criteria provided, conflicting classifications

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	May 27, 2022	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:1 Uncertain:1

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) -
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. -

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

Mar 16, 2023

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. Six other ClinVar submitters (evaluation after 2014) have cited the variant with conflicting assessments, classifying the variant as likely pathogenic (n = 4), pathogenic (n = 1), and uncertain significance (n = 1). 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	T
BayesDel_noAF	Benign	-0.20
Cadd	Benign	18
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.58	D
Eigen	Benign	-0.065
Eigen_PC	Benign	0.012
FATHMM_MKL	Benign	0.48	N
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.030	T
MetaSVM	Benign	-0.74	T
MutationAssessor	Uncertain	2.6	M
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.36
Sift	Benign	0.31	T
Sift4G	Benign	0.48	T
Polyphen		0.35	B
Vest4		0.22
MVP		0.92
MPC		0.014
ClinPred		0.86	D
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

Other links and lift over

dbSNP: rs114706984; hg19: chr3-165548187; COSMIC: COSV100011882;