2-63885572-CTTT-CTTTT

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP6

The NM_006759.4(UGP2):​c.576-5dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0241 in 976,892 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 Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.028 (0 hom.)
• Consequence: UGP2 NM_006759.4 splice_region, intron
• Clinical Significance: Likely benign no assertion criteria provided B:1
• 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 1 ACMG points.

• PM2: Variant has high frequency in the SAS (0.0467) population. However there is too low homozygotes in high coverage region: (expected more than 141, got 0).
• BP6: Variant 2-63885572-C-CT is Benign according to our data. Variant chr2-63885572-C-CT is described in ClinVar as Likely_benign. ClinVar VariationId is 3059622.Status of the report is no_assertion_criteria_provided, 0 stars.

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.576-5dupT		splice_region intron	N/A	NP_006750.3
	UGP2	NM_001001521.2		c.543-5dupT		splice_region intron	N/A	NP_001001521.1	Q16851-2
	UGP2	NM_001377524.1		c.543-5dupT		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.576-17_576-16insT		intron	N/A	ENSP00000338703.5	Q16851-1
	UGP2	ENST00000394417.7	TSL:1	c.543-17_543-16insT		intron	N/A	ENSP00000377939.2	Q16851-2
	UGP2	ENST00000467648.6	TSL:1	c.543-17_543-16insT		intron	N/A	ENSP00000420793.2	Q16851-2

Frequencies

GnomAD3 genomes AF: 0.00170 AC: 248 AN: 145924 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00411

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00233

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000871

Gnomad FIN AF: 0.00173

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000424

Gnomad OTH AF: 0.00101

GnomAD2 exomes AF: 0.0315 AC: 2666 AN: 84626 AF XY: 0.0313

Gnomad AFR exome AF: 0.0294

Gnomad AMR exome AF: 0.0449

Gnomad ASJ exome AF: 0.0583

Gnomad EAS exome AF: 0.0479

Gnomad FIN exome AF: 0.0285

Gnomad NFE exome AF: 0.0224

Gnomad OTH exome AF: 0.0526

GnomAD4 exome AF: 0.0280 AC: 23298 AN: 830894 Hom.: 0 Cov.: 18 AF XY: 0.0282 AC XY: 11674 AN XY: 413742

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

African (AFR) AF: 0.0343 AC: 629 AN: 18354

American (AMR) AF: 0.0258 AC: 476 AN: 18440

Ashkenazi Jewish (ASJ) AF: 0.0324 AC: 420 AN: 12966

East Asian (EAS) AF: 0.0259 AC: 623 AN: 24072

South Asian (SAS) AF: 0.0484 AC: 2275 AN: 47028

European-Finnish (FIN) AF: 0.0285 AC: 947 AN: 33244

Middle Eastern (MID) AF: 0.0198 AC: 76 AN: 3848

European-Non Finnish (NFE) AF: 0.0263 AC: 16798 AN: 638868

Other (OTH) AF: 0.0309 AC: 1054 AN: 34074

⚠️ 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: 0.00173 AC: 252 AN: 145998 Hom.: 0 Cov.: 32 AF XY: 0.00199 AC XY: 141 AN XY: 70934

African (AFR) AF: 0.00420 AC: 168 AN: 39980

American (AMR) AF: 0.00233 AC: 34 AN: 14594

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3372

East Asian (EAS) AF: 0.00 AC: 0 AN: 5044

South Asian (SAS) AF: 0.000874 AC: 4 AN: 4578

European-Finnish (FIN) AF: 0.00173 AC: 16 AN: 9252

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

European-Non Finnish (NFE) AF: 0.000424 AC: 28 AN: 65998

Other (OTH) AF: 0.00100 AC: 2 AN: 1992

Alfa AF: 0.00362 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	UGP2-related disorder (1)

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)		0.010		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: COSV61430809; COSMIC: COSV61430809;