NM_006759.4:c.576-5delT

Variant names:

• chr2-63885572-CT-C
• rs751800377
• NM_006759.4:c.576-5delT

Variant summary

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

The NM_006759.4(UGP2):​c.576-5delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0373 in 892,506 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as (no stars).

• Frequency:
  • Genomes: 𝑓 0.00042 (0 hom., cov: 32)
  • Exomes 𝑓: 0.045 (0 hom.)
• Consequence: UGP2 NM_006759.4 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.249
• Publications: 0 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: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

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

• PM2: Variant has high frequency in the SAS (0.0681) population. However there is too low homozygotes in high coverage region: (expected more than 311, got 0).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006759.4. 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
	UGP2	NM_006759.4	MANE Select	c.576-5delT		splice_region intron	N/A	NP_006750.3
	UGP2	NM_001001521.2		c.543-5delT		splice_region intron	N/A	NP_001001521.1	Q16851-2
	UGP2	NM_001377524.1		c.543-5delT		splice_region intron	N/A	NP_001364453.1	A0A140VKE1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UGP2	ENST00000337130.10	TSL:1 MANE Select	c.576-16delT		intron	N/A	ENSP00000338703.5	Q16851-1
	UGP2	ENST00000394417.7	TSL:1	c.543-16delT		intron	N/A	ENSP00000377939.2	Q16851-2
	UGP2	ENST00000467648.6	TSL:1	c.543-16delT		intron	N/A	ENSP00000420793.2	Q16851-2

Frequencies

GnomAD3 genomes AF: 0.000419 AC: 61 AN: 145642 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000451

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000137

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000791

Gnomad SAS AF: 0.000218

Gnomad FIN AF: 0.00153

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000319

Gnomad OTH AF: 0.000509

GnomAD2 exomes AF: 0.0620 AC: 5249 AN: 84626 AF XY: 0.0641

Gnomad AFR exome AF: 0.0451

Gnomad AMR exome AF: 0.0764

Gnomad ASJ exome AF: 0.125

Gnomad EAS exome AF: 0.0748

Gnomad FIN exome AF: 0.0534

Gnomad NFE exome AF: 0.0539

Gnomad OTH exome AF: 0.0840

GnomAD4 exome AF: 0.0446 AC: 33270 AN: 746790 Hom.: 0 Cov.: 18 AF XY: 0.0459 AC XY: 17085 AN XY: 372068

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

African (AFR) AF: 0.0425 AC: 706 AN: 16614

American (AMR) AF: 0.0471 AC: 780 AN: 16558

Ashkenazi Jewish (ASJ) AF: 0.0559 AC: 639 AN: 11438

East Asian (EAS) AF: 0.0482 AC: 1011 AN: 20980

South Asian (SAS) AF: 0.0702 AC: 3031 AN: 43178

European-Finnish (FIN) AF: 0.0497 AC: 1487 AN: 29946

Middle Eastern (MID) AF: 0.0350 AC: 125 AN: 3572

European-Non Finnish (NFE) AF: 0.0419 AC: 24054 AN: 574066

Other (OTH) AF: 0.0472 AC: 1437 AN: 30438

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000419 AC: 61 AN: 145716 Hom.: 0 Cov.: 32 AF XY: 0.000480 AC XY: 34 AN XY: 70784

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

African (AFR) AF: 0.000450 AC: 18 AN: 39972

American (AMR) AF: 0.000137 AC: 2 AN: 14562

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3368

East Asian (EAS) AF: 0.000793 AC: 4 AN: 5046

South Asian (SAS) AF: 0.000219 AC: 1 AN: 4576

European-Finnish (FIN) AF: 0.00153 AC: 14 AN: 9174

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 282

European-Non Finnish (NFE) AF: 0.000319 AC: 21 AN: 65846

Other (OTH) AF: 0.000504 AC: 1 AN: 1984

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00452 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.25
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs751800377; hg19: chr2-64112706; COSMIC: COSV61427840; COSMIC: COSV61427840;