rs71647871

Variant names:

• chr16-55823658-C-T
• rs71647871
• NM_001025195.2:c.431G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-55823658-C-T
• chr16-55823658-C-A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001025195.2(CES1):​c.431G>A​(p.Gly144Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.01 in 151,662 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as drug response (★★★).

• Frequency:
  • Genomes: 𝑓 0.010 (0 hom., cov: 39)
  • Exomes 𝑓: 0.012 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CES1 NM_001025195.2 missense
• Clinical Significance: drug response reviewed by expert panel P:1 B:1 O:2
• Conservation: PhyloP100: 0.892
• Publications: 140 publications found

Genes affected

CES1 (HGNC:1863): (carboxylesterase 1) This gene encodes a member of the carboxylesterase large family. The family members are responsible for the hydrolysis or transesterification of various xenobiotics, such as cocaine and heroin, and endogenous substrates with ester, thioester, or amide bonds. They may participate in fatty acyl and cholesterol ester metabolism, and may play a role in the blood-brain barrier system. This enzyme is the major liver enzyme and functions in liver drug clearance. Mutations of this gene cause carboxylesterase 1 deficiency. Three transcript variants encoding three different isoforms have been found for this gene. [provided by RefSeq, Jun 2010]

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03447321).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001025195.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CES1	NM_001025195.2	MANE Select	c.431G>A	p.Gly144Glu	missense	Exon 4 of 14	NP_001020366.1	P23141-2
	CES1	NM_001025194.2		c.428G>A	p.Gly143Glu	missense	Exon 4 of 14	NP_001020365.1	P23141-1
	CES1	NM_001266.5		c.428G>A	p.Gly143Glu	missense	Exon 4 of 14	NP_001257.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CES1	ENST00000360526.8	TSL:1 MANE Select	c.431G>A	p.Gly144Glu	missense	Exon 4 of 14	ENSP00000353720.4	P23141-2
	CES1	ENST00000361503.8	TSL:1	c.428G>A	p.Gly143Glu	missense	Exon 4 of 14	ENSP00000355193.4	P23141-1
	CES1	ENST00000422046.6	TSL:1	c.428G>A	p.Gly143Glu	missense	Exon 4 of 14	ENSP00000390492.2	P23141-3

Frequencies

GnomAD3 genomes AF: 0.0100 AC: 1519 AN: 151544 Hom.: 0 Cov.: 39

Gnomad AFR AF: 0.00237

Gnomad AMI AF: 0.00330

Gnomad AMR AF: 0.0106

Gnomad ASJ AF: 0.0235

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00685

Gnomad FIN AF: 0.0108

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0148

Gnomad OTH AF: 0.0101

GnomAD2 exomes AF: 0.0109 AC: 2725 AN: 249588 AF XY: 0.0112

Gnomad AFR exome AF: 0.00179

Gnomad AMR exome AF: 0.00693

Gnomad ASJ exome AF: 0.0260

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.0114

Gnomad NFE exome AF: 0.0148

Gnomad OTH exome AF: 0.0158

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0119 AC: 17324 AN: 1450200 Hom.: 0 Cov.: 35 AF XY: 0.0120 AC XY: 8645 AN XY: 721462

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00248 AC: 83 AN: 33448

American (AMR) AF: 0.00749 AC: 334 AN: 44588

Ashkenazi Jewish (ASJ) AF: 0.0257 AC: 663 AN: 25818

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39698

South Asian (SAS) AF: 0.00658 AC: 566 AN: 86044

European-Finnish (FIN) AF: 0.0127 AC: 674 AN: 52988

Middle Eastern (MID) AF: 0.0110 AC: 63 AN: 5732

European-Non Finnish (NFE) AF: 0.0129 AC: 14171 AN: 1101962

Other (OTH) AF: 0.0128 AC: 768 AN: 59922

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0100 AC: 1519 AN: 151662 Hom.: 0 Cov.: 39 AF XY: 0.00930 AC XY: 690 AN XY: 74154

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00236 AC: 98 AN: 41518

American (AMR) AF: 0.0106 AC: 161 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.0235 AC: 81 AN: 3440

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.00686 AC: 33 AN: 4814

European-Finnish (FIN) AF: 0.0108 AC: 114 AN: 10566

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

European-Non Finnish (NFE) AF: 0.0148 AC: 1002 AN: 67602

Other (OTH) AF: 0.0100 AC: 21 AN: 2098

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0134 Hom.: 0

ESP6500AA AF: 0.00114 AC: 5

ESP6500EA AF: 0.00942 AC: 81

ExAC AF: 0.0144 AC: 1747

ClinVar

ClinVar submissions

Significance: drug response

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
1	-	1	not provided (2)
-	-	-	clopidogrel response - Efficacy (1)
-	-	-	clopidogrel response - Metabolism/PK (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.59	D
Eigen	Benign	0.15
Eigen_PC	Benign	-0.15
FATHMM_MKL	Benign	0.72	D
LIST_S2	Uncertain	0.95	D
MetaRNN	Benign	0.034	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Pathogenic	3.2	M
PhyloP100		0.89
PrimateAI	Benign	0.40	T
PROVEAN	Pathogenic	-6.6	D
REVEL	Benign	0.24
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.29
MPC		0.23
ClinPred		0.059	T
GERP RS		1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.94
gMVP		0.73
Mutation Taster		=66/34	polymorphism

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: rs71647871; hg19: chr16-55857570; COSMIC: COSV107467882;