chr2-233713766-G-C

Position:

• chr2-233713766-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_019078.2(UGT1A5):​c.775G>C​(p.Gly259Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0908 in 1,587,116 control chromosomes in the GnomAD database, including 8,641 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.10 (897 hom., cov: 32)
  • Exomes 𝑓: 0.090 (7744 hom.)
• Consequence: UGT1A5 NM_019078.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.67

Genes affected

UGT1A5 (HGNC:12537): (UDP glucuronosyltransferase family 1 member A5) 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. [provided by RefSeq, Jul 2008]

UGT1A6 (HGNC:12538): (UDP glucuronosyltransferase family 1 member A6) 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 is active on phenolic and planar compounds. Alternative splicing in the unique 5' end of this gene results in two transcript variants. [provided by RefSeq, Jul 2008]

UGT1A10 (HGNC:12531): (UDP glucuronosyltransferase family 1 member A10) 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 on mycophenolic acid, coumarins, and quinolines. [provided by RefSeq, Jul 2008]

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]

UGT1A7 (HGNC:12539): (UDP glucuronosyltransferase family 1 member A7) 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 moderate glucuronidase activity with phenols. [provided by RefSeq, Jul 2008]

UGT1A9 (HGNC:12541): (UDP glucuronosyltransferase family 1 member A9) 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 is active on phenols. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0039182007).
• BP6: Variant 2-233713766-G-C is Benign according to our data. Variant chr2-233713766-G-C is described in ClinVar as [Benign]. Clinvar id is 770346.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.193 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UGT1A5	NM_019078.2	c.775G>C	p.Gly259Arg	missense_variant	1/5	ENST00000373414.4	NP_061951.1
UGT1A6	NM_001072.4	c.861+19901G>C		intron_variant		ENST00000305139.11	NP_001063.2
UGT1A10	NM_019075.4	c.856-53268G>C		intron_variant		ENST00000344644.10	NP_061948.1
UGT1A8	NM_019076.5	c.856-53268G>C		intron_variant		ENST00000373450.5	NP_061949.3
UGT1A7	NM_019077.3	c.855+30974G>C		intron_variant		ENST00000373426.4	NP_061950.2
UGT1A9	NM_021027.3	c.855+40977G>C		intron_variant		ENST00000354728.5	NP_066307.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UGT1A5	ENST00000373414.4	c.775G>C	p.Gly259Arg	missense_variant	1/5	1	NM_019078.2	ENSP00000362513	P1
UGT1A6	ENST00000305139.11	c.861+19901G>C		intron_variant		1	NM_001072.4	ENSP00000303174	P1
UGT1A10	ENST00000344644.10	c.856-53268G>C		intron_variant		1	NM_019075.4	ENSP00000343838	P1
UGT1A9	ENST00000354728.5	c.855+40977G>C		intron_variant		1	NM_021027.3	ENSP00000346768	P1
UGT1A7	ENST00000373426.4	c.855+30974G>C		intron_variant		1	NM_019077.3	ENSP00000362525	P1
UGT1A8	ENST00000373450.5	c.856-53268G>C		intron_variant		1	NM_019076.5	ENSP00000362549	P1

Frequencies

GnomAD3 genomes AF: 0.101 AC: 15401 AN: 151992 Hom.: 893 Cov.: 32

Gnomad AFR AF: 0.104

Gnomad AMI AF: 0.00769

Gnomad AMR AF: 0.112

Gnomad ASJ AF: 0.102

Gnomad EAS AF: 0.204

Gnomad SAS AF: 0.196

Gnomad FIN AF: 0.0599

Gnomad MID AF: 0.124

Gnomad NFE AF: 0.0902

Gnomad OTH AF: 0.111

GnomAD3 exomes AF: 0.0699 AC: 15694 AN: 224612 Hom.: 1873 AF XY: 0.0699 AC XY: 8423 AN XY: 120494

Gnomad AFR exome AF: 0.0690

Gnomad AMR exome AF: 0.0745

Gnomad ASJ exome AF: 0.0460

Gnomad EAS exome AF: 0.166

Gnomad SAS exome AF: 0.125

Gnomad FIN exome AF: 0.0425

Gnomad NFE exome AF: 0.0481

Gnomad OTH exome AF: 0.0681

GnomAD4 exome AF: 0.0897 AC: 128741 AN: 1435006 Hom.: 7744 Cov.: 34 AF XY: 0.0920 AC XY: 65540 AN XY: 712572

Gnomad4 AFR exome AF: 0.0963

Gnomad4 AMR exome AF: 0.107

Gnomad4 ASJ exome AF: 0.0892

Gnomad4 EAS exome AF: 0.161

Gnomad4 SAS exome AF: 0.181

Gnomad4 FIN exome AF: 0.0680

Gnomad4 NFE exome AF: 0.0798

Gnomad4 OTH exome AF: 0.0982

GnomAD4 genome AF: 0.101 AC: 15421 AN: 152110 Hom.: 897 Cov.: 32 AF XY: 0.102 AC XY: 7607 AN XY: 74358

Gnomad4 AFR AF: 0.104

Gnomad4 AMR AF: 0.112

Gnomad4 ASJ AF: 0.102

Gnomad4 EAS AF: 0.203

Gnomad4 SAS AF: 0.194

Gnomad4 FIN AF: 0.0599

Gnomad4 NFE AF: 0.0902

Gnomad4 OTH AF: 0.117

Alfa AF: 0.0923 Hom.: 253

Bravo AF: 0.103

ESP6500AA AF: 0.0338 AC: 149

ESP6500EA AF: 0.0212 AC: 182

ExAC AF: 0.115 AC: 13956

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 26, 2021	This variant is associated with the following publications: (PMID: 29710432) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 08, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	0.80
DANN	Benign	0.56
DEOGEN2	Benign	0.094	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.099	N
LIST_S2	Benign	0.022	T
MetaRNN	Benign	0.0039	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	M
MutationTaster	Benign	1.0	P;P;P;P;P;P;P;P;P
PROVEAN	Benign	-0.18	N
REVEL	Benign	0.063
Sift	Benign	0.23	T
Sift4G	Benign	0.30	T
Polyphen		0.0	B
Vest4		0.079
MutPred		0.31		Loss of sheet (P = 0.0228);
MPC		0.20
ClinPred		0.0026	T
GERP RS		-1.0
Varity_R		0.088
gMVP		0.57

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

LitVar

Other links and lift over

dbSNP: rs3892170; hg19: chr2-234622412; COSMIC: COSV59382206;