NM_000642.3:c.2001+8T>C

Variant names:

• chr1-99881185-T-C
• rs3736296
• NM_000642.3:c.2001+8T>C

Variant summary

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

The NM_000642.3(AGL):​c.2001+8T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.549 in 1,612,570 control chromosomes in the GnomAD database, including 245,309 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.52 (20668 hom., cov: 31)
  • Exomes 𝑓: 0.55 (224641 hom.)
• Consequence: AGL NM_000642.3 splice_region, intron
• Scores: Splicing: ADA: 0.00003241
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 2.08
• Publications: 15 publications found

Genes affected

AGL (HGNC:321): (amylo-alpha-1, 6-glucosidase, 4-alpha-glucanotransferase) This gene encodes the glycogen debrancher enzyme which is involved in glycogen degradation. This enzyme has two independent catalytic activities which occur at different sites on the protein: a 4-alpha-glucotransferase activity and a amylo-1,6-glucosidase activity. Mutations in this gene are associated with glycogen storage disease although a wide range of enzymatic and clinical variability occurs which may be due to tissue-specific alternative splicing. Alternatively spliced transcripts encoding different isoforms have been described. [provided by RefSeq, Jul 2008]

AGL Gene-Disease associations (from GenCC):

• glycogen storage disease III

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Ambry Genetics, Laboratory for Molecular Medicine, Myriad Women’s Health, Orphanet, G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae), Genomics England PanelApp

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 1-99881185-T-C is Benign according to our data. Variant chr1-99881185-T-C is described in ClinVar as Benign. ClinVar VariationId is 256725.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.656 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000642.3. 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
	AGL	NM_000642.3	MANE Select	c.2001+8T>C		splice_region intron	N/A	NP_000633.2
	AGL	NM_000028.3		c.2001+8T>C		splice_region intron	N/A	NP_000019.2
	AGL	NM_000643.3		c.2001+8T>C		splice_region intron	N/A	NP_000634.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGL	ENST00000361915.8	TSL:1 MANE Select	c.2001+8T>C		splice_region intron	N/A	ENSP00000355106.3
	AGL	ENST00000294724.8	TSL:1	c.2001+8T>C		splice_region intron	N/A	ENSP00000294724.4
	AGL	ENST00000370163.7	TSL:1	c.2001+8T>C		splice_region intron	N/A	ENSP00000359182.3

Frequencies

GnomAD3 genomes AF: 0.516 AC: 78283 AN: 151780 Hom.: 20631 Cov.: 31

Gnomad AFR AF: 0.425

Gnomad AMI AF: 0.464

Gnomad AMR AF: 0.565

Gnomad ASJ AF: 0.419

Gnomad EAS AF: 0.675

Gnomad SAS AF: 0.599

Gnomad FIN AF: 0.521

Gnomad MID AF: 0.443

Gnomad NFE AF: 0.547

Gnomad OTH AF: 0.515

GnomAD2 exomes AF: 0.554 AC: 139035 AN: 250904 AF XY: 0.553

Gnomad AFR exome AF: 0.431

Gnomad AMR exome AF: 0.622

Gnomad ASJ exome AF: 0.423

Gnomad EAS exome AF: 0.660

Gnomad FIN exome AF: 0.514

Gnomad NFE exome AF: 0.544

Gnomad OTH exome AF: 0.541

GnomAD4 exome AF: 0.552 AC: 806886 AN: 1460672 Hom.: 224641 Cov.: 37 AF XY: 0.553 AC XY: 401532 AN XY: 726678

African (AFR) AF: 0.425 AC: 14203 AN: 33454

American (AMR) AF: 0.612 AC: 27367 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.432 AC: 11286 AN: 26124

East Asian (EAS) AF: 0.676 AC: 26817 AN: 39668

South Asian (SAS) AF: 0.590 AC: 50850 AN: 86238

European-Finnish (FIN) AF: 0.523 AC: 27906 AN: 53400

Middle Eastern (MID) AF: 0.431 AC: 2486 AN: 5764

European-Non Finnish (NFE) AF: 0.552 AC: 613740 AN: 1110986

Other (OTH) AF: 0.534 AC: 32231 AN: 60348

GnomAD4 genome AF: 0.516 AC: 78361 AN: 151898 Hom.: 20668 Cov.: 31 AF XY: 0.518 AC XY: 38423 AN XY: 74230

African (AFR) AF: 0.425 AC: 17603 AN: 41400

American (AMR) AF: 0.565 AC: 8626 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.419 AC: 1452 AN: 3468

East Asian (EAS) AF: 0.675 AC: 3479 AN: 5156

South Asian (SAS) AF: 0.600 AC: 2890 AN: 4818

European-Finnish (FIN) AF: 0.521 AC: 5492 AN: 10546

Middle Eastern (MID) AF: 0.435 AC: 127 AN: 292

European-Non Finnish (NFE) AF: 0.547 AC: 37170 AN: 67944

Other (OTH) AF: 0.522 AC: 1101 AN: 2108

Alfa AF: 0.534 Hom.: 20344

Bravo AF: 0.515

Asia WGS AF: 0.633 AC: 2202 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Glycogen storage disease type III (4)
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	7.4
DANN	Benign	0.56
PhyloP100		2.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000032
dbscSNV1_RF	Benign	0.0020
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: rs3736296; hg19: chr1-100346741; COSMIC: COSV54049713; COSMIC: COSV54049713;