rs2230307

Variant names:

• chr1-99896369-G-A
• rs2230307
• NM_000642.3:c.3343G>A

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PP3 BP6_Very_Strong BA1

The NM_000642.3(AGL):​c.3343G>A​(p.Gly1115Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0576 in 1,613,468 control chromosomes in the GnomAD database, including 3,757 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. G1115G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.056 (344 hom., cov: 32)
  • Exomes 𝑓: 0.058 (3413 hom.)
• Consequence: AGL NM_000642.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 9.58
• Publications: 26 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: Ambry Genetics, ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, Laboratory for Molecular Medicine, Myriad Women’s Health

ACMG classification

Our verdict: Benign. The variant received -15 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 6: Cadd, Dann, Eigen, MutationAssessor, phyloP100way_vertebrate, PROVEAN [when BayesDel_addAF, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP6: Variant 1-99896369-G-A is Benign according to our data. Variant chr1-99896369-G-A is described in ClinVar as Benign. ClinVar VariationId is 256738.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.153 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGL	NM_000642.3	MANE Select	c.3343G>A	p.Gly1115Arg	missense	Exon 25 of 34	NP_000633.2	P35573-1
	AGL	NM_000028.3		c.3343G>A	p.Gly1115Arg	missense	Exon 25 of 34	NP_000019.2	P35573-1
	AGL	NM_000643.3		c.3343G>A	p.Gly1115Arg	missense	Exon 25 of 34	NP_000634.2	A0A0S2A4E4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGL	ENST00000361915.8	TSL:1 MANE Select	c.3343G>A	p.Gly1115Arg	missense	Exon 25 of 34	ENSP00000355106.3	P35573-1
	AGL	ENST00000294724.8	TSL:1	c.3343G>A	p.Gly1115Arg	missense	Exon 25 of 34	ENSP00000294724.4	P35573-1
	AGL	ENST00000370163.7	TSL:1	c.3343G>A	p.Gly1115Arg	missense	Exon 25 of 34	ENSP00000359182.3	P35573-1

Frequencies

GnomAD3 genomes AF: 0.0562 AC: 8550 AN: 152086 Hom.: 342 Cov.: 32

Gnomad AFR AF: 0.0288

Gnomad AMI AF: 0.0482

Gnomad AMR AF: 0.121

Gnomad ASJ AF: 0.0107

Gnomad EAS AF: 0.162

Gnomad SAS AF: 0.0496

Gnomad FIN AF: 0.0728

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0508

Gnomad OTH AF: 0.0612

GnomAD2 exomes AF: 0.0735 AC: 18478 AN: 251422 AF XY: 0.0672

Gnomad AFR exome AF: 0.0283

Gnomad AMR exome AF: 0.177

Gnomad ASJ exome AF: 0.0110

Gnomad EAS exome AF: 0.158

Gnomad FIN exome AF: 0.0699

Gnomad NFE exome AF: 0.0489

Gnomad OTH exome AF: 0.0572

GnomAD4 exome AF: 0.0577 AC: 84341 AN: 1461264 Hom.: 3413 Cov.: 31 AF XY: 0.0566 AC XY: 41177 AN XY: 727008

African (AFR) AF: 0.0278 AC: 929 AN: 33462

American (AMR) AF: 0.171 AC: 7629 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0125 AC: 326 AN: 26130

East Asian (EAS) AF: 0.185 AC: 7356 AN: 39662

South Asian (SAS) AF: 0.0479 AC: 4132 AN: 86250

European-Finnish (FIN) AF: 0.0700 AC: 3737 AN: 53398

Middle Eastern (MID) AF: 0.0232 AC: 134 AN: 5766

European-Non Finnish (NFE) AF: 0.0510 AC: 56726 AN: 1111502

Other (OTH) AF: 0.0559 AC: 3372 AN: 60370

GnomAD4 genome AF: 0.0562 AC: 8556 AN: 152204 Hom.: 344 Cov.: 32 AF XY: 0.0586 AC XY: 4361 AN XY: 74426

African (AFR) AF: 0.0287 AC: 1193 AN: 41534

American (AMR) AF: 0.121 AC: 1852 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0107 AC: 37 AN: 3470

East Asian (EAS) AF: 0.162 AC: 837 AN: 5164

South Asian (SAS) AF: 0.0492 AC: 237 AN: 4818

European-Finnish (FIN) AF: 0.0728 AC: 772 AN: 10602

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0508 AC: 3457 AN: 68010

Other (OTH) AF: 0.0597 AC: 126 AN: 2112

Alfa AF: 0.0532 Hom.: 1070

Bravo AF: 0.0599

TwinsUK AF: 0.0564 AC: 209

ALSPAC AF: 0.0446 AC: 172

ESP6500AA AF: 0.0261 AC: 115

ESP6500EA AF: 0.0498 AC: 428

ExAC AF: 0.0688 AC: 8357

Asia WGS AF: 0.111 AC: 384 AN: 3478

EpiCase AF: 0.0436

EpiControl AF: 0.0412

ClinVar

ClinVar submissions

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
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Uncertain	-0.030
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.37	T
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
MetaRNN	Benign	0.0033	T
MetaSVM	Uncertain	0.37	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		9.6
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-7.4	D
REVEL	Uncertain	0.57
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.040	D
Polyphen		1.0	D
Vest4		0.45
MutPred		0.59		Gain of MoRF binding (P = 0.0134)
MPC		0.31
ClinPred		0.057	T
GERP RS		5.9
Varity_R		0.83
gMVP		0.92
Mutation Taster		=96/4	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.36		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.36		Position offset: 19

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2230307; hg19: chr1-100361925; COSMIC: COSV54048879;