4-69599313-C-T

Variant names:

• chr4-69599313-C-T
• rs374804650
• NM_001105677.2:c.824G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001105677.2(UGT2A2):​c.824G>A​(p.Arg275His) variant causes a missense change. The variant allele was found at a frequency of 0.0000917 in 1,613,740 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. R275R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000083 (0 hom.)
• Consequence: UGT2A2 NM_001105677.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.88
• Publications: 6 publications found

Genes affected

UGT2A2 (HGNC:28183): (UDP glucuronosyltransferase family 2 member A2) The protein encoded by this gene belongs to the UDP-glycosyltransferase family. Members of this protein family play a role in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. The encoded enzyme is expressed in the olfactory neuroepithelium, which lines the posterior nasal cavity and is exposed to a wide range of odorants and airborne toxic compounds. Hence, this protein has been suggested to be involved in clearing lipophilic odorant molecules from the sensory epithelium. This gene shares exon structure with the UDP glucuronosyltransferase 2A1 family member, which encodes N-terminally distinct isoforms. Polymorphisms in this gene may be associated with the loss of taste and smell that is reported by some individuals during SARS-CoV-2 infection. [provided by RefSeq, Jan 2022]

UGT2A1 (HGNC:12542): (UDP glucuronosyltransferase family 2 member A1 complex locus) The protein encoded by this gene belongs to the UDP-glycosyltransferase family. Members of this protein family play a role in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. The encoded enzyme is expressed in the olfactory neuroepithelium, which lines the posterior nasal cavity and is exposed to a wide range of odorants and airborne toxic compounds. Hence, this protein has been suggested to be involved in clearing lipophilic odorant molecules from the sensory epithelium. This gene shares exon structure with the UDP glucuronosyltransferase 2A2 family member, which encodes N-terminally distinct isoforms. Polymorphisms in this gene may be associated with the loss of taste and smell that is reported by some individuals during SARS-CoV-2 infection. [provided by RefSeq, Jan 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.11490613).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001105677.2. 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
	UGT2A2	NM_001105677.2	MANE Select	c.824G>A	p.Arg275His	missense	Exon 2 of 6	NP_001099147.2	P0DTE5-1
	UGT2A1	NM_001252275.3	MANE Select	c.929G>A	p.Arg310His	missense	Exon 4 of 7	NP_001239204.2	P0DTE4-5
	UGT2A1	NM_001389565.1		c.1427G>A	p.Arg476His	missense	Exon 4 of 8	NP_001376494.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UGT2A2	ENST00000604629.6	TSL:1 MANE Select	c.824G>A	p.Arg275His	missense	Exon 2 of 6	ENSP00000475028.2	P0DTE5-1
	UGT2A1	ENST00000286604.9	TSL:1 MANE Select	c.929G>A	p.Arg310His	missense	Exon 4 of 7	ENSP00000286604.4	P0DTE4-5
	UGT2A1	ENST00000503640.5	TSL:1	c.797G>A	p.Arg266His	missense	Exon 2 of 6	ENSP00000424478.1	P0DTE4-1

Frequencies

GnomAD3 genomes AF: 0.000171 AC: 26 AN: 152014 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000435

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000328

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000191 AC: 48 AN: 250758 AF XY: 0.000177

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.00113

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000353

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000835 AC: 122 AN: 1461608 Hom.: 0 Cov.: 30 AF XY: 0.0000798 AC XY: 58 AN XY: 727092

African (AFR) AF: 0.000358 AC: 12 AN: 33474

American (AMR) AF: 0.00112 AC: 50 AN: 44658

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.000378 AC: 15 AN: 39674

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53390

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000351 AC: 39 AN: 1111906

Other (OTH) AF: 0.0000828 AC: 5 AN: 60384

GnomAD4 genome AF: 0.000171 AC: 26 AN: 152132 Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74364

African (AFR) AF: 0.000434 AC: 18 AN: 41512

American (AMR) AF: 0.000327 AC: 5 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10574

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68010

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000147 Hom.: 0

Bravo AF: 0.000242

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000148 AC: 18

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	22
DANN	Benign	0.90
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.13
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.44	T
PhyloP100		5.9
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.25
Sift	Benign	0.47	T
Sift4G	Benign	0.23	T
Polyphen		1.0	D
Vest4		0.65
MVP		0.40
MPC		0.011
ClinPred		0.13	T
GERP RS		2.9
gMVP		0.54
Mutation Taster		=67/33	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: rs374804650; hg19: chr4-70465031; COSMIC: COSV54143462;