rs754214624
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000055.4(BCHE):βc.1027_1028insAβ(p.Thr343AsnfsTer8) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000812 in 1,613,672 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (β β ). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: π 0.00014 ( 0 hom., cov: 32)
Exomes π: 0.000075 ( 0 hom. )
Consequence
BCHE
NM_000055.4 frameshift
NM_000055.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 3.65
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
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Very rare variant in population databases, with high coverage;
PP5
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Variant 3-165830006-G-GT is Pathogenic according to our data. Variant chr3-165830006-G-GT is described in ClinVar as [Likely_pathogenic]. Clinvar id is 370302.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BCHE | NM_000055.4 | c.1027_1028insA | p.Thr343AsnfsTer8 | frameshift_variant | 2/4 | ENST00000264381.8 | |
BCHE | NR_137636.2 | n.1145_1146insA | non_coding_transcript_exon_variant | 2/5 | |||
BCHE | NR_137635.2 | n.110+7307_110+7308insA | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BCHE | ENST00000264381.8 | c.1027_1028insA | p.Thr343AsnfsTer8 | frameshift_variant | 2/4 | 1 | NM_000055.4 | P1 | |
LINC01322 | ENST00000651449.1 | n.1008-15879dup | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes ? AF: 0.000138 AC: 21AN: 152038Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000962 AC: 24AN: 249444Hom.: 0 AF XY: 0.0000665 AC XY: 9AN XY: 135320
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GnomAD4 exome AF: 0.0000753 AC: 110AN: 1461516Hom.: 0 Cov.: 31 AF XY: 0.0000715 AC XY: 52AN XY: 727042
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GnomAD4 genome ? AF: 0.000138 AC: 21AN: 152156Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12AN XY: 74368
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Deficiency of butyrylcholinesterase Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Jan 05, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 15, 2024 | Variant summary: BCHE c.1027dupA (p.Thr343AsnfsX8) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 9.6e-05 in 249444 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in BCHE causing Deficiency Of Butyrylcholine Esterase (9.6e-05 vs 0.016), allowing no conclusion about variant significance. c.1027dupA has been reported in the literature in the compound heterozygous state in at least one individual affected with hypocholinesterasemia (e.g. Iida_1995). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 8680411). ClinVar contains an entry for this variant (Variation ID: 370302). Based on the evidence outlined above, the variant was classified as pathogenic. - |
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at