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: 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 -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGL	NM_000642.3	c.3343G>A	p.Gly1115Arg	missense_variant	Exon 25 of 34	ENST00000361915.8	NP_000633.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGL	ENST00000361915.8	c.3343G>A	p.Gly1115Arg	missense_variant	Exon 25 of 34	1	NM_000642.3	ENSP00000355106.3

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

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glycogen storage disease type III Benign:4

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:2

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 29, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:2

Oct 26, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

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;T;T;T;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;.;.;.;D
MetaRNN	Benign	0.0033	T;T;T;T;T
MetaSVM	Uncertain	0.37	D
MutationAssessor	Pathogenic	3.1	M;M;M;M;.
PhyloP100		9.6
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-7.4	D;D;D;D;D
REVEL	Uncertain	0.57
Sift	Uncertain	0.0030	D;D;D;D;D
Sift4G	Uncertain	0.040	D;D;D;D;D
Polyphen		1.0	D;D;D;D;D
Vest4		0.45
MutPred		0.59		Gain of MoRF binding (P = 0.0134);Gain of MoRF binding (P = 0.0134);Gain of MoRF binding (P = 0.0134);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;