2-63856320-A-G

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong

The NM_001001521.2(UGP2):c.1A>G(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000384 in 1,612,832 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000039 ( 0 hom. )

Consequence

UGP2
NM_001001521.2 start_lost

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11

Conservation

PhyloP100: 3.18

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PVS1

Start lost variant, next in-frame start position is after 3 pathogenic variants. Next in-frame start position is after 110 codons. Genomic position: 63882571. Lost 0.220 part of the original CDS.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 2-63856320-A-G is Pathogenic according to our data. Variant chr2-63856320-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 805980.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-63856320-A-G is described in Lovd as [Likely_pathogenic]. Variant chr2-63856320-A-G is described in Lovd as [Pathogenic]. Variant chr2-63856320-A-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UGP2	NM_006759.4 link	c.34A>G	p.Met12Val	missense_variant	Exon 2 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.34A>G	p.Met12Val	missense_variant	Exon 2 of 10	1	NM_006759.4	ENSP00000338703.5		Q16851-1

Frequencies

GnomAD3 genomes

AF:

0.0000328

AC:

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000561

AC:

AN:

249502

Hom.:

AF XY:

0.0000742

AC XY:

AN XY:

134860

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000548

Gnomad SAS exome

AF:

0.000396

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000884

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000390

AC:

AN:

1460622

Hom.:

Cov.:

AF XY:

0.0000592

AC XY:

AN XY:

726610

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000488

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000989

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152210

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000621

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000508

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000659

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy, 83

Pathogenic:9

Jun 30, 2022

Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 19, 2023

Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This homozygous start loss variant identified in 7 month female with refractory seizure, pneumonia, GDD with west syndrome. This nucleotide change has an allele frequency of 0.0053% in gnomAD aggregate database [PM2]. This variant has a clinvar entry with Pathogenic/Likely Pathogenic interpretation by multiple submitter [PP5]. Clinvar variation ID: 805980. PMID: 31820119. Based on available evidence the variant is classified as "Pathogenic". -

Oct 21, 2020

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Dec 08, 2023

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.005%). Predicted Consequence/Location: Missense changes are a common disease-causing mechanism. Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 31820119). In silico tool predictions suggest no damaging effect of the variant on gene or gene product [REVEL: 0.17 (<0.4); 3Cnet: 0.06 (<0.15, specificity 0.78 and negative predicitive value 0.92)]. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000805980 /PMID: 31820119).The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (PMID: 31820119). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

May 06, 2021

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0106 - This gene is associated with autosomal recessive disease. (I) 0206 - Variant is predicted to result in a loss of the canonical translation initiation codon (ATG). (SP) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (15 heterozygotes, 0 homozygotes). (SP) 0705 - No comparable variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in 22 individuals from 15 families (PMID: 31820119). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. The absence of the shorter isoform leads to a reduction of functional UGP2 enzyme in neural stem cells and leads to altered glycogen metabolims (PMID: 31820119). (SP) 1102 - Strong phenotype match for this individual. (SP) 1209 - This variant has been shown to be both maternally and paternally inherited (biallelic) by trio analysis. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Mar 29, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 19, 2021

Undiagnosed Diseases Network, NIH

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The missense variant p.M12V in UGP2 (NM_006759.3) has been previously reported as a recurrent homozygous mutation in similarly affected patients (Perenthaler E et al). The variant causes a disruption of the start codon of the shorter isoform, which is predominant in brain and hence leads to disease as proved by functional studies on zebrafish (Perenthaler E et al). The p.M12V variant is observed in 12/30,282 (0.0396%) alleles from individuals of South Asian background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. It has been submiited to ClinVar as Pathogenic. For these reasons, this variant has been classified as Pathogenic. -

Oct 04, 2024

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

PS3,PP1,PM3(strong),PM2,PP3 -

D-6618

Pathogenic:1

Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Homozygous missense variation in exon 2 of UGP2 gene that result in the amino acid substitution of caline for methionine at codon 21 was detected. The in silico prediction of the variant is benign by PolyPhen-2 (HumDiv), SIFT, LRT and MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as a variant of uncertain significance. -

not provided

Pathogenic:1

Aug 18, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 12 of the UGP2 protein (p.Met12Val). This variant is present in population databases (rs768305634, gnomAD 0.04%). This missense change has been observed in individuals with clinical features of UGP2-related developmental and epileptic encephalopathy (PMID: 31820119; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 805980). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. Experimental studies have shown that this missense change affects UGP2 function (PMID: 31820119). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.054

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.12

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.032

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

Eigen

Benign

-0.24

Eigen_PC

Benign

0.018

FATHMM_MKL

Uncertain

0.81

LIST_S2

Uncertain

0.93

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

M_CAP

Benign

0.0054

MetaRNN

Benign

0.12

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

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.0

.;.;.;.;.;L;.;.;.;.;.;.;.;.;.

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-0.71

N;N;N;N;D;N;.;N;.;.;N;N;N;N;.

REVEL

Benign

0.17

Sift

Benign

0.054

T;D;T;T;D;T;.;T;.;.;T;T;T;T;.

Sift4G

Benign

0.75

T;D;T;T;D;T;.;T;D;D;T;T;T;T;T

Polyphen

0.0

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

Vest4

0.59

MutPred

0.26

.;.;.;.;.;.;.;.;.;.;Loss of helix (P = 0.1299);.;.;.;.;

MVP

0.32

MPC

0.52

ClinPred

0.079

GERP RS

6.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.37

gMVP

0.48

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over