chr2-63882637-G-A

Variant names:

• chr2-63882637-G-A
• rs144988193
• NM_006759.4:c.427G>A

Variant summary

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

The NM_006759.4(UGP2):​c.427G>A​(p.Val143Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000706 in 1,417,122 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V143L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: UGP2 NM_006759.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.19
• Publications: 3 publications found

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

ACMG classification

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	c.427G>A	p.Val143Ile	missense_variant	Exon 4 of 10	ENST00000337130.10	NP_006750.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UGP2	ENST00000337130.10	c.427G>A	p.Val143Ile	missense_variant	Exon 4 of 10	1	NM_006759.4	ENSP00000338703.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.06e-7 AC: 1 AN: 1417122 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 698096

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32642

American (AMR) AF: 0.00 AC: 0 AN: 42158

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25314

East Asian (EAS) AF: 0.00 AC: 0 AN: 38778

South Asian (SAS) AF: 0.00 AC: 0 AN: 79782

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52664

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5594

European-Non Finnish (NFE) AF: 9.24e-7 AC: 1 AN: 1081756

Other (OTH) AF: 0.00 AC: 0 AN: 58434

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.16	.;.;T;.;T;.;T;T;T;.
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	0.98	.;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.013	T
MetaRNN	Uncertain	0.56	D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	.;.;L;.;.;.;.;.;.;.
PhyloP100		8.2
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-0.68	N;N;N;N;N;N;N;N;N;.
REVEL	Benign	0.15
Sift	Benign	0.10	T;T;D;D;T;D;T;T;T;.
Sift4G	Benign	0.18	T;T;T;T;T;T;T;T;T;T
Polyphen		0.47, 0.28	.;.;P;.;.;B;.;.;.;.
Vest4		0.31
MutPred		0.75		.;.;.;.;.;Loss of catalytic residue at E156 (P = 0.3829);.;.;.;.;
MVP		0.35
MPC		1.1
ClinPred		0.94	D
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.18
gMVP		0.57
Mutation Taster		=82/18	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: rs144988193; hg19: chr2-64109771;