rs114706984
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP5BP4BS2
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
Consequence
NM_000055.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
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: 377AN: 152084Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00211 AC: 527AN: 250210Hom.: 1 AF XY: 0.00208 AC XY: 281AN XY: 135374
GnomAD4 exome AF: 0.00391 AC: 5714AN: 1461688Hom.: 11 Cov.: 31 AF XY: 0.00370 AC XY: 2690AN XY: 727118
GnomAD4 genome ? AF: 0.00247 AC: 376AN: 152202Hom.: 0 Cov.: 32 AF XY: 0.00214 AC XY: 159AN XY: 74406
ClinVar
Submissions by phenotype
Deficiency of butyrylcholinesterase Pathogenic:3
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 - |
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. - |
not provided Pathogenic:1Uncertain: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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at