rs17121403

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000642.3(AGL):c.686A>G(p.Gln229Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0242 in 1,613,906 control chromosomes in the GnomAD database, including 969 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.043 ( 259 hom., cov: 32)

Exomes 𝑓: 0.022 ( 710 hom. )

Consequence

AGL
NM_000642.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 1.68

Publications

17 publications found

Variant links:

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

AGL links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.0018741786).

BP6

Variant 1-99870421-A-G is Benign according to our data. Variant chr1-99870421-A-G is described in ClinVar as Benign. ClinVar VariationId is 256749.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0934 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGL	NM_000642.3 link	c.686A>G	p.Gln229Arg	missense_variant	Exon 6 of 34	ENST00000361915.8	NP_000633.2	P35573-1A0A0S2A4E4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGL	ENST00000361915.8 link	c.686A>G	p.Gln229Arg	missense_variant	Exon 6 of 34	1	NM_000642.3	ENSP00000355106.3		P35573-1

Frequencies

GnomAD3 genomes

AF:

0.0426

AC:

6475

AN:

152160

Hom.:

250

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0953

Gnomad AMI

AF:

0.0471

Gnomad AMR

AF:

0.0599

Gnomad ASJ

AF:

0.00605

Gnomad EAS

AF:

0.0333

Gnomad SAS

AF:

0.0192

Gnomad FIN

AF:

0.00461

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0168

Gnomad OTH

AF:

0.0416

GnomAD2 exomes

AF:

0.0338

AC:

8504

AN:

251232

AF XY:

0.0291

show subpopulations

Gnomad AFR exome

AF:

0.0945

Gnomad AMR exome

AF:

0.104

Gnomad ASJ exome

AF:

0.00715

Gnomad EAS exome

AF:

0.0269

Gnomad FIN exome

AF:

0.00582

Gnomad NFE exome

AF:

0.0165

Gnomad OTH exome

AF:

0.0256

GnomAD4 exome

AF:

0.0222

AC:

32486

AN:

1461628

Hom.:

710

Cov.:

AF XY:

0.0213

AC XY:

15520

AN XY:

727134

show subpopulations

African (AFR)

AF:

0.0968

AC:

3238

AN:

33466

American (AMR)

AF:

0.0985

AC:

4406

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00781

AC:

204

AN:

26130

East Asian (EAS)

AF:

0.0389

AC:

1543

AN:

39658

South Asian (SAS)

AF:

0.0205

AC:

1771

AN:

86250

European-Finnish (FIN)

AF:

0.00646

AC:

345

AN:

53414

Middle Eastern (MID)

AF:

0.0101

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0176

AC:

19515

AN:

1111838

Other (OTH)

AF:

0.0233

AC:

1406

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

1544

3087

4631

6174

7718

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

850

1700

2550

3400

4250

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0428

AC:

6513

AN:

152278

Hom.:

259

Cov.:

AF XY:

0.0430

AC XY:

3199

AN XY:

74462

show subpopulations

African (AFR)

AF:

0.0959

AC:

3983

AN:

41546

American (AMR)

AF:

0.0601

AC:

918

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00605

AC:

AN:

3472

East Asian (EAS)

AF:

0.0334

AC:

173

AN:

5182

South Asian (SAS)

AF:

0.0190

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00461

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0168

AC:

1141

AN:

68020

Other (OTH)

AF:

0.0412

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

300

600

899

1199

1499

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

132

198

264

330

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0278

Hom.:

362

Bravo

AF:

0.0511

TwinsUK

AF:

0.0194

AC:

ALSPAC

AF:

0.0184

AC:

ESP6500AA

AF:

0.0876

AC:

386

ESP6500EA

AF:

0.0188

AC:

162

ExAC

AF:

0.0326

AC:

3953

Asia WGS

AF:

0.0350

AC:

121

AN:

3476

EpiCase

AF:

0.0168

EpiControl

AF:

0.0164

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Glycogen storage disease type III

Benign:5

Jul 15, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Aug 01, 2017

Phosphorus, Inc.

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. -

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 10, 2015

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

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Dec 15, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.52

CADD

Benign

(source)

DANN

Benign

0.70

DEOGEN2

Benign

0.029

T;T;T;T;.

Eigen

Benign

-0.59

Eigen_PC

Benign

-0.41

FATHMM_MKL

Benign

0.32

LIST_S2

Uncertain

0.86

D;.;.;.;D

MetaRNN

Benign

0.0019

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.71

N;N;N;N;.

PhyloP100

1.7

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.40

N;N;N;N;N

REVEL

Benign

0.12

Sift

Benign

0.86

T;T;T;T;T

Sift4G

Benign

0.53

T;T;T;T;T

Polyphen

0.0

B;B;B;B;B

Vest4

0.043

MPC

0.043

ClinPred

0.0016

GERP RS

4.2

Varity_R

0.039

gMVP

0.59

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over