4-69595226-C-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate 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. 12/18 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, single submitter B:1
• Conservation: PhyloP100: -0.196

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

Verdict is Benign. Variant got -10 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 id is 717876.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UGT2A2	NM_001105677.2	c.1047G>T	p.Lys349Asn	missense_variant	4/6	ENST00000604629.6
UGT2A1	NM_001252275.3	c.1020G>T	p.Lys340Asn	missense_variant	5/7	ENST00000286604.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UGT2A2	ENST00000604629.6	c.1047G>T	p.Lys349Asn	missense_variant	4/6	1	NM_001105677.2	P1
UGT2A1	ENST00000286604.9	c.1020G>T	p.Lys340Asn	missense_variant	5/7	1	NM_001252275.3

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

GnomAD3 exomes AF: 0.00248 AC: 621 AN: 250476 Hom.: 3 AF XY: 0.00270 AC XY: 366 AN XY: 135506

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 SAS exome AF: 0.000457

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

Gnomad4 AFR exome AF: 0.000448

Gnomad4 AMR exome AF: 0.00148

Gnomad4 ASJ exome AF: 0.00134

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000383

Gnomad4 FIN exome AF: 0.00161

Gnomad4 NFE exome AF: 0.00477

Gnomad4 OTH exome AF: 0.00411

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

Gnomad4 AFR AF: 0.000842

Gnomad4 AMR AF: 0.00150

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.000566

Gnomad4 NFE AF: 0.00426

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00365 Hom.: 1

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

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

May 11, 2018

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Computational scores

Source: dbNSFP v4.3

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
M_CAP	Benign	0.0078	T
MetaRNN	Benign	0.0042	T;T;T;T;T;T
MetaSVM	Benign	-0.97	T
PrimateAI	Benign	0.31	T
PROVEAN	Uncertain	-4.0	D;D;D;D;.;.
REVEL	Benign	0.044
Sift	Benign	0.17	T;T;T;T;.;.
Sift4G	Benign	0.13	T;T;T;T;T;T
Polyphen		0.0010	.;B;.;.;.;.
Vest4		0.17
MutPred		0.41		Loss of methylation at K340 (P = 0.0203);.;.;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

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

Publications

LitVar

Other links and lift over

dbSNP: rs146912371; hg19: chr4-70460944; COSMIC: COSV105143724; COSMIC: COSV105143724;