rs12149359

Variant names:

• chr16-55832988-T-C
• rs12149359
• NM_001025195.2:c.52+16A>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001025195.2(CES1):​c.52+16A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0201 in 1,460,812 control chromosomes in the GnomAD database, including 5,612 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.14 (1799 hom., cov: 31)
  • Exomes 𝑓: 0.0072 (3813 hom.)
• Consequence: CES1 NM_001025195.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.765
• Publications: 8 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BS2: High Homozygotes in GnomAd4 at 1799 AD,AR gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CES1	NM_001025195.2	MANE Select	c.52+16A>G		intron	N/A	NP_001020366.1
	CES1	NM_001025194.2		c.52+16A>G		intron	N/A	NP_001020365.1
	CES1	NM_001266.5		c.52+16A>G		intron	N/A	NP_001257.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CES1	ENST00000360526.8	TSL:1 MANE Select	c.52+16A>G		intron	N/A	ENSP00000353720.4
	CES1	ENST00000361503.8	TSL:1	c.52+16A>G		intron	N/A	ENSP00000355193.4
	CES1	ENST00000422046.6	TSL:1	c.52+16A>G		intron	N/A	ENSP00000390492.2

Frequencies

GnomAD3 genomes AF: 0.142 AC: 19765 AN: 139670 Hom.: 1796 Cov.: 31

Gnomad AFR AF: 0.135

Gnomad AMI AF: 0.0388

Gnomad AMR AF: 0.116

Gnomad ASJ AF: 0.133

Gnomad EAS AF: 0.203

Gnomad SAS AF: 0.153

Gnomad FIN AF: 0.132

Gnomad MID AF: 0.225

Gnomad NFE AF: 0.149

Gnomad OTH AF: 0.151

GnomAD2 exomes AF: 0.00797 AC: 1906 AN: 239034 AF XY: 0.00794

Gnomad AFR exome AF: 0.00807

Gnomad AMR exome AF: 0.00472

Gnomad ASJ exome AF: 0.00320

Gnomad EAS exome AF: 0.0245

Gnomad FIN exome AF: 0.00934

Gnomad NFE exome AF: 0.00609

Gnomad OTH exome AF: 0.0103

GnomAD4 exome AF: 0.00722 AC: 9533 AN: 1321026 Hom.: 3813 Cov.: 31 AF XY: 0.00811 AC XY: 5334 AN XY: 657882

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

African (AFR) AF: 0.00752 AC: 229 AN: 30468

American (AMR) AF: 0.00597 AC: 254 AN: 42542

Ashkenazi Jewish (ASJ) AF: 0.00677 AC: 162 AN: 23926

East Asian (EAS) AF: 0.0212 AC: 698 AN: 32982

South Asian (SAS) AF: 0.0222 AC: 1729 AN: 77842

European-Finnish (FIN) AF: 0.0212 AC: 961 AN: 45318

Middle Eastern (MID) AF: 0.0138 AC: 67 AN: 4842

European-Non Finnish (NFE) AF: 0.00494 AC: 4985 AN: 1009098

Other (OTH) AF: 0.00830 AC: 448 AN: 54008

⚠️ 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: 0.141 AC: 19777 AN: 139786 Hom.: 1799 Cov.: 31 AF XY: 0.140 AC XY: 9520 AN XY: 68132

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

African (AFR) AF: 0.135 AC: 5133 AN: 37994

American (AMR) AF: 0.116 AC: 1648 AN: 14210

Ashkenazi Jewish (ASJ) AF: 0.133 AC: 431 AN: 3248

East Asian (EAS) AF: 0.203 AC: 896 AN: 4418

South Asian (SAS) AF: 0.151 AC: 644 AN: 4268

European-Finnish (FIN) AF: 0.132 AC: 1275 AN: 9646

Middle Eastern (MID) AF: 0.238 AC: 61 AN: 256

European-Non Finnish (NFE) AF: 0.149 AC: 9355 AN: 62932

Other (OTH) AF: 0.156 AC: 299 AN: 1912

⚠️ 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: 0.105 Hom.: 287

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	8.6
DANN	Benign	0.58
PhyloP100		-0.77
PromoterAI		-0.11	Neutral
Mutation Taster		=100/0	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: rs12149359; hg19: chr16-55866900; COSMIC: COSV62085664; COSMIC: COSV62085664;