Genetic Variant NM_006759.4:c.455C>T (chr2-63883973-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_006759.4(UGP2):c.455C>T(p.Thr152Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000276 in 1,451,430 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

UGP2
NM_006759.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.97

Publications

0 publications found

Variant links:

Genes affected

UGP2 (HGNC:12527): (UDP-glucose pyrophosphorylase 2) The enzyme encoded by this gene is an important intermediary in mammalian carbohydrate interconversions. It transfers a glucose moiety from glucose-1-phosphate to MgUTP and forms UDP-glucose and MgPPi. In liver and muscle tissue, UDP-glucose is a direct precursor of glycogen; in lactating mammary gland it is converted to UDP-galactose which is then converted to lactose. The eukaryotic enzyme has no significant sequence similarity to the prokaryotic enzyme. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

UGP2 Gene-Disease associations (from GenCC):

developmental and epileptic encephalopathy, 83
Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P

UGP2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UGP2	NM_006759.4 link	c.455C>T	p.Thr152Ile	missense_variant	Exon 5 of 10	ENST00000337130.10	NP_006750.3	Q16851-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UGP2	ENST00000337130.10 link	c.455C>T	p.Thr152Ile	missense_variant	Exon 5 of 10	1	NM_006759.4	ENSP00000338703.5		Q16851-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000276

AC:

AN:

1451430

Hom.:

Cov.:

AF XY:

0.00000277

AC XY:

AN XY:

721346

show subpopulations

African (AFR)

AF:

0.0000304

AC:

AN:

32868

American (AMR)

AF:

0.00

AC:

AN:

42238

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25898

East Asian (EAS)

AF:

0.00

AC:

AN:

39422

South Asian (SAS)

AF:

0.0000361

AC:

AN:

83200

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53234

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5734

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1108792

Other (OTH)

AF:

0.00

AC:

AN:

60044

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Jan 23, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.455C>T (p.T152I) alteration is located in exon 5 (coding exon 5) of the UGP2 gene. This alteration results from a C to T substitution at nucleotide position 455, causing the threonine (T) at amino acid position 152 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.078

BayesDel_noAF

Benign

-0.35

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.29

.;.;T;T;.;T;T;T;.

Eigen

Uncertain

0.20

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.96

.;D;D;D;D;D;D;D;D

M_CAP

Benign

0.016

MetaRNN

Uncertain

0.49

T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.6

.;.;M;.;.;.;.;.;.

PhyloP100

4.0

PrimateAI

Uncertain

0.75

PROVEAN

Uncertain

-4.0

D;D;D;D;D;D;D;D;.

REVEL

Benign

0.14

Sift

Benign

0.043

D;D;D;D;D;D;D;D;.

Sift4G

Benign

0.14

T;T;T;T;T;T;T;T;T

Polyphen

0.0030, 0.026

.;.;B;.;B;.;.;.;.

Vest4

0.33

MutPred

0.45

.;.;.;.;Gain of catalytic residue at T161 (P = 0.0012);.;.;.;.;

MVP

0.43

MPC

0.67

ClinPred

0.96

GERP RS

5.7

Varity_R

0.42

gMVP

0.50

Mutation Taster

=19/81

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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NM_006759.4:c.455C>T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over