chr4-69595226-C-A

Variant names:

• chr4-69595226-C-A
• rs146912371
• NM_001105677.2:c.1047G>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001105677.2(UGT2A2):​c.1047G>T​(p.Lys349Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00382 in 1,613,714 control chromosomes in the GnomAD database, including 14 homozygotes. 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0025 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0040 (14 hom.)
• Consequence: UGT2A2 NM_001105677.2 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.196
• Publications: 5 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: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0041841567).
• BP6: Variant 4-69595226-C-A is Benign according to our data. Variant chr4-69595226-C-A is described in ClinVar as Likely_benign. ClinVar VariationId is 717876.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 14 gene

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.1047G>T	p.Lys349Asn	missense	Exon 4 of 6	NP_001099147.2	P0DTE5-1
	UGT2A1	NM_001252275.3	MANE Select	c.1020G>T	p.Lys340Asn	missense	Exon 5 of 7	NP_001239204.2	P0DTE4-5
	UGT2A1	NM_001389565.1		c.1650G>T	p.Lys550Asn	missense	Exon 6 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.1047G>T	p.Lys349Asn	missense	Exon 4 of 6	ENSP00000475028.2	P0DTE5-1
	UGT2A1	ENST00000286604.9	TSL:1 MANE Select	c.1020G>T	p.Lys340Asn	missense	Exon 5 of 7	ENSP00000286604.4	P0DTE4-5
	UGT2A1	ENST00000503640.5	TSL:1	c.1020G>T	p.Lys340Asn	missense	Exon 4 of 6	ENSP00000424478.1	P0DTE4-1

Frequencies

GnomAD3 genomes AF: 0.00250 AC: 380 AN: 152120 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000869

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00151

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.000566

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00428

Gnomad OTH AF: 0.00526

GnomAD2 exomes AF: 0.00248 AC: 621 AN: 250476 AF XY: 0.00270

Gnomad AFR exome AF: 0.000616

Gnomad AMR exome AF: 0.00142

Gnomad ASJ exome AF: 0.00159

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00185

Gnomad NFE exome AF: 0.00427

Gnomad OTH exome AF: 0.00164

GnomAD4 exome AF: 0.00396 AC: 5788 AN: 1461478 Hom.: 14 Cov.: 31 AF XY: 0.00386 AC XY: 2809 AN XY: 727046

African (AFR) AF: 0.000448 AC: 15 AN: 33462

American (AMR) AF: 0.00148 AC: 66 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00134 AC: 35 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39602

South Asian (SAS) AF: 0.000383 AC: 33 AN: 86248

European-Finnish (FIN) AF: 0.00161 AC: 86 AN: 53390

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5764

European-Non Finnish (NFE) AF: 0.00477 AC: 5303 AN: 1111812

Other (OTH) AF: 0.00411 AC: 248 AN: 60374

GnomAD4 genome AF: 0.00248 AC: 378 AN: 152236 Hom.: 0 Cov.: 32 AF XY: 0.00231 AC XY: 172 AN XY: 74426

African (AFR) AF: 0.000842 AC: 35 AN: 41546

American (AMR) AF: 0.00150 AC: 23 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4826

European-Finnish (FIN) AF: 0.000566 AC: 6 AN: 10592

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

European-Non Finnish (NFE) AF: 0.00426 AC: 290 AN: 68010

Other (OTH) AF: 0.00520 AC: 11 AN: 2114

Alfa AF: 0.00358 Hom.: 3

Bravo AF: 0.00245

TwinsUK AF: 0.00431 AC: 16

ALSPAC AF: 0.00441 AC: 17

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00384 AC: 33

ExAC AF: 0.00241 AC: 293

EpiCase AF: 0.00409

EpiControl AF: 0.00332

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	17
DANN	Uncertain	0.97
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.46	N
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.0078	T
MetaRNN	Benign	0.0042	T
MetaSVM	Benign	-0.97	T
PhyloP100		-0.20
PrimateAI	Benign	0.31	T
PROVEAN	Uncertain	-4.0	D
REVEL	Benign	0.044
Sift	Benign	0.17	T
Sift4G	Benign	0.13	T
Polyphen		0.0010	B
Vest4		0.17
MutPred		0.41		Loss of methylation at K340 (P = 0.0203)
MVP		0.11
MPC		0.012
ClinPred		0.012	T
GERP RS		0.39
gMVP		0.22
Mutation Taster		=87/13	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs146912371; hg19: chr4-70460944; COSMIC: COSV105143724; COSMIC: COSV105143724;