chr2-233713736-G-C

Position:

• chr2-233713736-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_019078.2(UGT1A5):​c.745G>C​(p.Val249Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0909 in 1,587,106 control chromosomes in the GnomAD database, including 8,660 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 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 (881 hom., cov: 32)
  • Exomes 𝑓: 0.090 (7779 hom.)
• Consequence: UGT1A5 NM_019078.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.95

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0038383305).
• BP6: Variant 2-233713736-G-C is Benign according to our data. Variant chr2-233713736-G-C is described in ClinVar as [Benign]. Clinvar id is 770345.Status of the report is criteria_provided_single_submitter, 1 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.745G>C	p.Val249Leu	missense_variant	1/5	ENST00000373414.4	NP_061951.1
UGT1A6	NM_001072.4	c.861+19871G>C		intron_variant		ENST00000305139.11	NP_001063.2
UGT1A10	NM_019075.4	c.856-53298G>C		intron_variant		ENST00000344644.10	NP_061948.1
UGT1A8	NM_019076.5	c.856-53298G>C		intron_variant		ENST00000373450.5	NP_061949.3
UGT1A7	NM_019077.3	c.855+30944G>C		intron_variant		ENST00000373426.4	NP_061950.2
UGT1A9	NM_021027.3	c.855+40947G>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.745G>C	p.Val249Leu	missense_variant	1/5	1	NM_019078.2	ENSP00000362513	P1
UGT1A6	ENST00000305139.11	c.861+19871G>C		intron_variant		1	NM_001072.4	ENSP00000303174	P1
UGT1A10	ENST00000344644.10	c.856-53298G>C		intron_variant		1	NM_019075.4	ENSP00000343838	P1
UGT1A9	ENST00000354728.5	c.855+40947G>C		intron_variant		1	NM_021027.3	ENSP00000346768	P1
UGT1A7	ENST00000373426.4	c.855+30944G>C		intron_variant		1	NM_019077.3	ENSP00000362525	P1
UGT1A8	ENST00000373450.5	c.856-53298G>C		intron_variant		1	NM_019076.5	ENSP00000362549	P1

Frequencies

GnomAD3 genomes AF: 0.101 AC: 15356 AN: 151918 Hom.: 877 Cov.: 32

Gnomad AFR AF: 0.104

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.111

Gnomad ASJ AF: 0.102

Gnomad EAS AF: 0.203

Gnomad SAS AF: 0.195

Gnomad FIN AF: 0.0599

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.0900

Gnomad OTH AF: 0.110

GnomAD3 exomes AF: 0.0720 AC: 16217 AN: 225282 Hom.: 1908 AF XY: 0.0718 AC XY: 8666 AN XY: 120764

Gnomad AFR exome AF: 0.0668

Gnomad AMR exome AF: 0.0758

Gnomad ASJ exome AF: 0.0461

Gnomad EAS exome AF: 0.173

Gnomad SAS exome AF: 0.126

Gnomad FIN exome AF: 0.0452

Gnomad NFE exome AF: 0.0505

Gnomad OTH exome AF: 0.0679

GnomAD4 exome AF: 0.0898 AC: 128932 AN: 1435070 Hom.: 7779 Cov.: 34 AF XY: 0.0921 AC XY: 65651 AN XY: 712552

Gnomad4 AFR exome AF: 0.0954

Gnomad4 AMR exome AF: 0.109

Gnomad4 ASJ exome AF: 0.0887

Gnomad4 EAS exome AF: 0.164

Gnomad4 SAS exome AF: 0.180

Gnomad4 FIN exome AF: 0.0687

Gnomad4 NFE exome AF: 0.0798

Gnomad4 OTH exome AF: 0.0986

GnomAD4 genome AF: 0.101 AC: 15376 AN: 152036 Hom.: 881 Cov.: 32 AF XY: 0.102 AC XY: 7579 AN XY: 74332

Gnomad4 AFR AF: 0.104

Gnomad4 AMR AF: 0.111

Gnomad4 ASJ AF: 0.102

Gnomad4 EAS AF: 0.203

Gnomad4 SAS AF: 0.194

Gnomad4 FIN AF: 0.0599

Gnomad4 NFE AF: 0.0900

Gnomad4 OTH AF: 0.116

Alfa AF: 0.0938 Hom.: 253

Bravo AF: 0.103

ESP6500AA AF: 0.0288 AC: 127

ESP6500EA AF: 0.0262 AC: 225

ExAC AF: 0.116 AC: 14088

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

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	Benign	0.099
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.0010
DANN	Benign	0.49
DEOGEN2	Benign	0.037	T
Eigen	Benign	-1.9
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.047	T
MetaRNN	Benign	0.0038	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.9	N
MutationTaster	Benign	1.0	P;P;P;P;P;P;P;P;P
PROVEAN	Benign	1.3	N
REVEL	Benign	0.070
Sift	Benign	0.53	T
Sift4G	Benign	0.73	T
Polyphen		0.0	B
Vest4		0.017
MPC		0.16
ClinPred		0.0012	T
GERP RS		-7.1
Varity_R		0.031
gMVP		0.26

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: rs17862868; hg19: chr2-234622382; COSMIC: COSV59382197;