2-233618225-C-G

Variant names:

• chr2-233618225-C-G
• rs1042597
• NM_019076.5:c.518C>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_019076.5(UGT1A8):​c.518C>G​(p.Ala173Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.255 in 1,613,732 control chromosomes in the GnomAD database, including 56,357 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.22 (4431 hom., cov: 31)
  • Exomes 𝑓: 0.26 (51926 hom.)
• Consequence: UGT1A8 NM_019076.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.179
• Publications: 50 publications found

Genes affected

UGT1A8 (HGNC:12540): (UDP glucuronosyltransferase family 1 member A8) This gene encodes a UDP-glucuronosyltransferase, an enzyme of the glucuronidation pathway that transforms small lipophilic molecules, such as steroids, bilirubin, hormones, and drugs, into water-soluble, excretable metabolites. This gene is part of a complex locus that encodes several UDP-glucuronosyltransferases. The locus includes thirteen unique alternate first exons followed by four common exons. Four of the alternate first exons are considered pseudogenes. Each of the remaining nine 5' exons may be spliced to the four common exons, resulting in nine proteins with different N-termini and identical C-termini. Each first exon encodes the substrate binding site, and is regulated by its own promoter. The enzyme encoded by this gene has glucuronidase activity with many substrates including coumarins, phenols, anthraquinones, flavones, and some opioids. [provided by RefSeq, Jul 2008]

UGT1A (HGNC:12529):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=8.2069635E-4).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.504 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_019076.5. 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
	UGT1A8	NM_019076.5	MANE Select	c.518C>G	p.Ala173Gly	missense	Exon 1 of 5	NP_061949.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UGT1A8	ENST00000373450.5	TSL:1 MANE Select	c.518C>G	p.Ala173Gly	missense	Exon 1 of 5	ENSP00000362549.4	Q9HAW9-1

Frequencies

GnomAD3 genomes AF: 0.216 AC: 32747 AN: 151932 Hom.: 4422 Cov.: 31

Gnomad AFR AF: 0.0734

Gnomad AMI AF: 0.204

Gnomad AMR AF: 0.289

Gnomad ASJ AF: 0.253

Gnomad EAS AF: 0.521

Gnomad SAS AF: 0.288

Gnomad FIN AF: 0.195

Gnomad MID AF: 0.316

Gnomad NFE AF: 0.257

Gnomad OTH AF: 0.242

GnomAD2 exomes AF: 0.271 AC: 68080 AN: 251176 AF XY: 0.273

Gnomad AFR exome AF: 0.0677

Gnomad AMR exome AF: 0.324

Gnomad ASJ exome AF: 0.244

Gnomad EAS exome AF: 0.512

Gnomad FIN exome AF: 0.204

Gnomad NFE exome AF: 0.258

Gnomad OTH exome AF: 0.277

GnomAD4 exome AF: 0.259 AC: 378713 AN: 1461682 Hom.: 51926 Cov.: 40 AF XY: 0.260 AC XY: 189043 AN XY: 727152

African (AFR) AF: 0.0663 AC: 2220 AN: 33472

American (AMR) AF: 0.319 AC: 14286 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.246 AC: 6437 AN: 26132

East Asian (EAS) AF: 0.546 AC: 21667 AN: 39688

South Asian (SAS) AF: 0.278 AC: 24004 AN: 86246

European-Finnish (FIN) AF: 0.213 AC: 11393 AN: 53420

Middle Eastern (MID) AF: 0.316 AC: 1820 AN: 5764

European-Non Finnish (NFE) AF: 0.253 AC: 281210 AN: 1111866

Other (OTH) AF: 0.260 AC: 15676 AN: 60380

GnomAD4 genome AF: 0.216 AC: 32768 AN: 152050 Hom.: 4431 Cov.: 31 AF XY: 0.218 AC XY: 16195 AN XY: 74318

African (AFR) AF: 0.0733 AC: 3044 AN: 41520

American (AMR) AF: 0.289 AC: 4416 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.253 AC: 877 AN: 3464

East Asian (EAS) AF: 0.521 AC: 2681 AN: 5150

South Asian (SAS) AF: 0.289 AC: 1392 AN: 4810

European-Finnish (FIN) AF: 0.195 AC: 2065 AN: 10574

Middle Eastern (MID) AF: 0.327 AC: 96 AN: 294

European-Non Finnish (NFE) AF: 0.257 AC: 17491 AN: 67958

Other (OTH) AF: 0.246 AC: 520 AN: 2114

Alfa AF: 0.209 Hom.: 1216

Bravo AF: 0.217

TwinsUK AF: 0.262 AC: 973

ALSPAC AF: 0.255 AC: 982

ESP6500AA AF: 0.0783 AC: 345

ESP6500EA AF: 0.247 AC: 2127

ExAC AF: 0.267 AC: 32460

Asia WGS AF: 0.393 AC: 1363 AN: 3478

EpiCase AF: 0.266

EpiControl AF: 0.256

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	6.4
DANN	Benign	0.84
DEOGEN2	Benign	0.21	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.079	N
LIST_S2	Benign	0.0070	T
MetaRNN	Benign	0.00082	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.45	N
PhyloP100		-0.18
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.034
Sift	Benign	0.10	T
Sift4G	Benign	0.23	T
Polyphen		0.044	B
Vest4		0.031
ClinPred		0.0033	T
GERP RS		-0.18
Varity_R		0.042
gMVP		0.14
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: rs1042597; hg19: chr2-234526871; COSMIC: COSV65074697;