NM_000055.4:c.293A>G

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 5P and 1B. PS3PP5BP4

The NM_000055.4(BCHE):c.293A>G(p.Asp98Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.016 in 1,613,944 control chromosomes in the GnomAD database, including 246 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV000967600: "In vitro functional studies provide evidence that the p.Asp98Gly variant impacts BCHE enzyme activity." PMID:9047329, PMID:27551784" and additional evidence is available in ClinVar.

Frequency

Genomes: 𝑓 0.012 ( 18 hom., cov: 32)

Exomes 𝑓: 0.016 ( 228 hom. )

Consequence

BCHE
NM_000055.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:21B:1O:3

Conservation

PhyloP100: 7.23

Publications

130 publications found

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 was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV000967600: "In vitro functional studies provide evidence that the p.Asp98Gly variant impacts BCHE enzyme activity." PMID:9047329, PMID:27551784; SCV001370742: Experimental evidence evaluating an impact on protein function demonstrated the variant negatively affects enzyme activity and concentration, causing a reduction in substrate affinity and an abolition of substrate activation (e.g. Delacour_2014, Lockridge_2016, Masson_1999).; SCV004046421: Functional studies suggest the c.293A>G (p.Asp98Gly) variant leads to reduced enzyme activity and binding affinity for succinylcholine (PMID: 25448037, 2915989).; SCV002004685: Published functional studies demonstrate a severe reduction in affinity for butyrylthiocholine and succinyldithiocholine (PMID: 9047329, 23123771); SCV003799857: Functional studies show the variant causes reduced enzyme activity and a reduction in substrate affinity/activation (Delacour 2014, Lockridge 2016, Masson 1999). PMID: 25054547 PMID: 27551784 PMID: 10446378

PP5

Variant 3-165830741-T-C is Pathogenic according to our data. Variant chr3-165830741-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 13215.

BP4

Computational evidence support a benign effect (MetaRNN=0.006447643). . Strength limited to SUPPORTING due to the PP5.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000055.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
BCHE	NM_000055.4	MANE Select	c.293A>G	p.Asp98Gly	missense	Exon 2 of 4	NP_000046.1	P06276
BCHE	NR_137636.2		n.411A>G		non_coding_transcript_exon	Exon 2 of 5
BCHE	NR_137635.2		n.110+6573A>G		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
BCHE	ENST00000264381.8	TSL:1 MANE Select	c.293A>G	p.Asp98Gly	missense	Exon 2 of 4	ENSP00000264381.3	P06276
BCHE	ENST00000479451.5	TSL:1	c.107+6573A>G		intron	N/A	ENSP00000418325.1	H0Y885
BCHE	ENST00000855337.1		c.293A>G	p.Asp98Gly	missense	Exon 2 of 5	ENSP00000525396.1

Frequencies

GnomAD3 genomes

AF:

0.0125

AC:

1897

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00364

Gnomad AMI

AF:

0.0143

Gnomad AMR

AF:

0.0131

Gnomad ASJ

AF:

0.0164

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00186

Gnomad FIN

AF:

0.0135

Gnomad MID

AF:

0.0443

Gnomad NFE

AF:

0.0187

Gnomad OTH

AF:

0.0186

GnomAD2 exomes

AF:

0.0121

AC:

3044

AN:

250996

AF XY:

0.0125

show subpopulations

Gnomad AFR exome

AF:

0.00369

Gnomad AMR exome

AF:

0.00905

Gnomad ASJ exome

AF:

0.0174

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.0123

Gnomad NFE exome

AF:

0.0179

Gnomad OTH exome

AF:

0.0173

GnomAD4 exome

AF:

0.0164

AC:

23967

AN:

1461658

Hom.:

228

Cov.:

AF XY:

0.0161

AC XY:

11725

AN XY:

727124

show subpopulations

African (AFR)

AF:

0.00293

AC:

AN:

33442

American (AMR)

AF:

0.00922

AC:

412

AN:

44672

Ashkenazi Jewish (ASJ)

AF:

0.0165

AC:

432

AN:

26120

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39694

South Asian (SAS)

AF:

0.00363

AC:

313

AN:

86250

European-Finnish (FIN)

AF:

0.0115

AC:

614

AN:

53410

Middle Eastern (MID)

AF:

0.0257

AC:

148

AN:

5766

European-Non Finnish (NFE)

AF:

0.0190

AC:

21079

AN:

1111918

Other (OTH)

AF:

0.0144

AC:

869

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

1502

3003

4505

6006

7508

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

818

1636

2454

3272

4090

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0124

AC:

1894

AN:

152286

Hom.:

Cov.:

AF XY:

0.0121

AC XY:

901

AN XY:

74468

show subpopulations

African (AFR)

AF:

0.00363

AC:

151

AN:

41570

American (AMR)

AF:

0.0131

AC:

200

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.0164

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00207

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0135

AC:

143

AN:

10608

Middle Eastern (MID)

AF:

0.0408

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0187

AC:

1269

AN:

68018

Other (OTH)

AF:

0.0184

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

196

293

391

489

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0162

Hom.:

Bravo

AF:

0.0124

TwinsUK

AF:

0.0191

AC:

ALSPAC

AF:

0.0179

AC:

ESP6500AA

AF:

0.00227

AC:

ESP6500EA

AF:

0.0199

AC:

171

ExAC

AF:

0.0121

AC:

1465

Asia WGS

AF:

0.00289

AC:

AN:

3478

EpiCase

AF:

0.0211

EpiControl

AF:

0.0195

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Deficiency of butyrylcholinesterase (15)

not provided (8)

BCHE-related disorder (1)

Postanesthetic apnea (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.43

BayesDel_addAF

Benign

-0.0050

BayesDel_noAF

Pathogenic

0.23

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.59

Eigen

Uncertain

0.34

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.87

MetaRNN

Benign

0.0064

MetaSVM

Benign

-0.30

MutationAssessor

Benign

1.9

PhyloP100

7.2

PrimateAI

Benign

0.48

PROVEAN

Pathogenic

-5.6

REVEL

Uncertain

0.56

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0040

Polyphen

0.69

Vest4

0.27

MPC

0.11

ClinPred

0.062

GERP RS

5.8

Varity_R

0.92

gMVP

0.74

Mutation Taster

=74/26

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

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