rs16849700

Variant names:

• chr3-165830185-C-G
• rs16849700
• NM_000055.4:c.849G>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_000055.4(BCHE):​c.849G>C​(p.Glu283Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0153 in 1,613,926 control chromosomes in the GnomAD database, including 330 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 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 0.023 (78 hom., cov: 32)
  • Exomes 𝑓: 0.015 (252 hom.)
• Consequence: BCHE NM_000055.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -0.296
• Publications: 7 publications found

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

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0018603504).
• BP6: Variant 3-165830185-C-G is Benign according to our data. Variant chr3-165830185-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 254777.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0537 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BCHE	NM_000055.4	c.849G>C	p.Glu283Asp	missense_variant	Exon 2 of 4	ENST00000264381.8	NP_000046.1
BCHE	NR_137636.2	n.967G>C		non_coding_transcript_exon_variant	Exon 2 of 5
BCHE	NR_137635.2	n.110+7129G>C		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BCHE	ENST00000264381.8	c.849G>C	p.Glu283Asp	missense_variant	Exon 2 of 4	1	NM_000055.4	ENSP00000264381.3

Frequencies

GnomAD3 genomes AF: 0.0227 AC: 3459 AN: 152124 Hom.: 78 Cov.: 32

Gnomad AFR AF: 0.0557

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00951

Gnomad ASJ AF: 0.0133

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0228

Gnomad FIN AF: 0.00160

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0115

Gnomad OTH AF: 0.0234

GnomAD2 exomes AF: 0.0147 AC: 3685 AN: 250568 AF XY: 0.0147

Gnomad AFR exome AF: 0.0585

Gnomad AMR exome AF: 0.00817

Gnomad ASJ exome AF: 0.0121

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00222

Gnomad NFE exome AF: 0.0122

Gnomad OTH exome AF: 0.0162

GnomAD4 exome AF: 0.0146 AC: 21296 AN: 1461684 Hom.: 252 Cov.: 31 AF XY: 0.0147 AC XY: 10707 AN XY: 727128

African (AFR) AF: 0.0632 AC: 2114 AN: 33462

American (AMR) AF: 0.00864 AC: 386 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.0111 AC: 289 AN: 26132

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39694

South Asian (SAS) AF: 0.0266 AC: 2293 AN: 86248

European-Finnish (FIN) AF: 0.00247 AC: 132 AN: 53416

Middle Eastern (MID) AF: 0.0435 AC: 251 AN: 5766

European-Non Finnish (NFE) AF: 0.0133 AC: 14785 AN: 1111888

Other (OTH) AF: 0.0173 AC: 1043 AN: 60392

GnomAD4 genome AF: 0.0228 AC: 3464 AN: 152242 Hom.: 78 Cov.: 32 AF XY: 0.0222 AC XY: 1649 AN XY: 74440

African (AFR) AF: 0.0556 AC: 2311 AN: 41538

American (AMR) AF: 0.00949 AC: 145 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.0133 AC: 46 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5176

South Asian (SAS) AF: 0.0230 AC: 111 AN: 4828

European-Finnish (FIN) AF: 0.00160 AC: 17 AN: 10626

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0115 AC: 779 AN: 68012

Other (OTH) AF: 0.0232 AC: 49 AN: 2114

Alfa AF: 0.0138 Hom.: 16

Bravo AF: 0.0255

TwinsUK AF: 0.0105 AC: 39

ALSPAC AF: 0.0127 AC: 49

ESP6500AA AF: 0.0567 AC: 250

ESP6500EA AF: 0.0126 AC: 108

ExAC AF: 0.0157 AC: 1907

Asia WGS AF: 0.0120 AC: 42 AN: 3478

EpiCase AF: 0.0131

EpiControl AF: 0.0146

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Deficiency of butyrylcholinesterase Uncertain:1 Benign:1

Apr 05, 2017

Counsyl

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not specified Benign:2

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 22, 2022

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: BCHE c.849G>C (p.Glu283Asp) results in a conservative amino acid change located in the Carboxylesterase, type B domain (IPR002018) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.015 in 250568 control chromosomes, predominantly at a frequency of 0.059 within the African or African-American subpopulation in the gnomAD database, including 18 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 3.7 fold of the estimated maximal expected allele frequency for a pathogenic variant in BCHE causing Deficiency Of Butyrylcholine Esterase phenotype (0.016), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.849G>C has been reported in the literature but these report(s) do not provide unequivocal conclusions about association of the variant with Deficiency Of Butyrylcholine Esterase (example, Jasiecki_2016). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as benign and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	1.2
DANN	Benign	0.51
DEOGEN2	Benign	0.17	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.052	N
LIST_S2	Benign	0.61	T
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.20	N
PhyloP100		-0.30
PrimateAI	Benign	0.26	T
PROVEAN	Benign	0.61	N
REVEL	Benign	0.069
Sift	Benign	0.82	T
Sift4G	Benign	0.68	T
Polyphen		0.0	B
Vest4		0.025
MutPred		0.16		Loss of disorder (P = 0.1294);
MPC		0.014
ClinPred		0.00093	T
GERP RS		-4.6
Varity_R		0.17
gMVP		0.26
Mutation Taster		=93/7	polymorphism (auto)

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

Other links and lift over

dbSNP: rs16849700; hg19: chr3-165547973; COSMIC: COSV52263259;