rs2229520

Variant names:

• chr3-81536998-G-A
• rs2229520
• NM_000158.4:c.1716C>T

Your query was ambiguous. Multiple possible variants found:

• chr3-81536998-G-A
• chr3-81536998-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000158.4(GBE1):​c.1716C>T​(p.Asp572Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00279 in 1,591,780 control chromosomes in the GnomAD database, including 114 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (69 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (45 hom.)
• Consequence: GBE1 NM_000158.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 1.20
• Publications: 1 publications found

Genes affected

GBE1 (HGNC:4180): (1,4-alpha-glucan branching enzyme 1) The protein encoded by this gene is a glycogen branching enzyme that catalyzes the transfer of alpha-1,4-linked glucosyl units from the outer end of a glycogen chain to an alpha-1,6 position on the same or a neighboring glycogen chain. Branching of the chains is essential to increase the solubility of the glycogen molecule and, consequently, in reducing the osmotic pressure within cells. Highest level of this enzyme are found in liver and muscle. Mutations in this gene are associated with glycogen storage disease IV (also known as Andersen's disease). [provided by RefSeq, Jul 2008]

GBE1 Gene-Disease associations (from GenCC):

• glycogen storage disease due to glycogen branching enzyme deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Laboratory for Molecular Medicine, Ambry Genetics, G2P, ClinGen
• adult polyglucosan body disease

  Inheritance: AR Classification: MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 3-81536998-G-A is Benign according to our data. Variant chr3-81536998-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 255385.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0534 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000158.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GBE1	NM_000158.4	MANE Select	c.1716C>T	p.Asp572Asp	synonymous	Exon 13 of 16	NP_000149.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GBE1	ENST00000429644.7	TSL:1 MANE Select	c.1716C>T	p.Asp572Asp	synonymous	Exon 13 of 16	ENSP00000410833.2
	GBE1	ENST00000895874.1		c.1710C>T	p.Asp570Asp	synonymous	Exon 13 of 16	ENSP00000565933.1
	GBE1	ENST00000942742.1		c.1710C>T	p.Asp570Asp	synonymous	Exon 13 of 16	ENSP00000612801.1

Frequencies

GnomAD3 genomes AF: 0.0148 AC: 2256 AN: 151942 Hom.: 69 Cov.: 32

Gnomad AFR AF: 0.0518

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00486

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.0134

GnomAD2 exomes AF: 0.00365 AC: 841 AN: 230684 AF XY: 0.00281

Gnomad AFR exome AF: 0.0527

Gnomad AMR exome AF: 0.00267

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000125

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000151

Gnomad OTH exome AF: 0.00129

GnomAD4 exome AF: 0.00151 AC: 2180 AN: 1439720 Hom.: 45 Cov.: 30 AF XY: 0.00125 AC XY: 898 AN XY: 715596

African (AFR) AF: 0.0555 AC: 1773 AN: 31920

American (AMR) AF: 0.00290 AC: 120 AN: 41420

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25790

East Asian (EAS) AF: 0.0000792 AC: 3 AN: 37878

South Asian (SAS) AF: 0.000220 AC: 18 AN: 81970

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53180

Middle Eastern (MID) AF: 0.00105 AC: 6 AN: 5708

European-Non Finnish (NFE) AF: 0.0000826 AC: 91 AN: 1102300

Other (OTH) AF: 0.00284 AC: 169 AN: 59554

GnomAD4 genome AF: 0.0148 AC: 2255 AN: 152060 Hom.: 69 Cov.: 32 AF XY: 0.0139 AC XY: 1035 AN XY: 74326

African (AFR) AF: 0.0516 AC: 2142 AN: 41502

American (AMR) AF: 0.00486 AC: 74 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5154

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 67948

Other (OTH) AF: 0.0132 AC: 28 AN: 2114

Alfa AF: 0.00651 Hom.: 18

Bravo AF: 0.0169

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Glycogen storage disease, type IV (2)
-	-	2	not specified (2)
-	-	1	Adult polyglucosan body disease (1)
-	-	1	Glycogen storage disease, type IV;C1849722:Adult polyglucosan body disease (1)
-	-	1	Glycogen storage disease, type IV;C1856301:Glycogen storage disease IV, classic hepatic (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	8.5
DANN	Benign	0.52
PhyloP100		1.2
Mutation Taster		=100/0	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: rs2229520; hg19: chr3-81586149; COSMIC: COSV107525038;