NM_000642.3:c.2522C>T

Variant names:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_000642.3(AGL):c.2522C>T(p.Ser841Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00204 in 1,612,178 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S841Y) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0023 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0020 ( 10 hom. )

Consequence

AGL
NM_000642.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 5.68

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010740131).

BP6

Variant 1-99884427-C-T is Benign according to our data. Variant chr1-99884427-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 256727.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Benign=2, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00228 (346/151948) while in subpopulation AMR AF= 0.0036 (55/15266). AF 95% confidence interval is 0.00284. There are 2 homozygotes in gnomad4. There are 158 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGL	NM_000642.3 link	c.2522C>T	p.Ser841Phe	missense_variant	Exon 19 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.2522C>T	p.Ser841Phe	missense_variant	Exon 19 of 34	1	NM_000642.3	ENSP00000355106.3		P35573-1

Frequencies

GnomAD3 genomes

AF:

0.00228

AC:

346

AN:

151830

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000291

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00361

Gnomad ASJ

AF:

0.0141

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00352

Gnomad FIN

AF:

0.000380

Gnomad MID

AF:

0.0348

Gnomad NFE

AF:

0.00271

Gnomad OTH

AF:

0.00671

GnomAD3 exomes

AF:

0.00277

AC:

689

AN:

248886

Hom.:

AF XY:

0.00300

AC XY:

405

AN XY:

135100

show subpopulations

Gnomad AFR exome

AF:

0.000257

Gnomad AMR exome

AF:

0.00183

Gnomad ASJ exome

AF:

0.0151

Gnomad EAS exome

AF:

0.0000546

Gnomad SAS exome

AF:

0.00295

Gnomad FIN exome

AF:

0.000186

Gnomad NFE exome

AF:

0.00307

Gnomad OTH exome

AF:

0.00512

GnomAD4 exome

AF:

0.00201

AC:

2938

AN:

1460230

Hom.:

Cov.:

AF XY:

0.00217

AC XY:

1576

AN XY:

726484

show subpopulations

Gnomad4 AFR exome

AF:

0.00123

Gnomad4 AMR exome

AF:

0.00199

Gnomad4 ASJ exome

AF:

0.0150

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00326

Gnomad4 FIN exome

AF:

0.000301

Gnomad4 NFE exome

AF:

0.00161

Gnomad4 OTH exome

AF:

0.00365

GnomAD4 genome

AF:

0.00228

AC:

346

AN:

151948

Hom.:

Cov.:

AF XY:

0.00213

AC XY:

158

AN XY:

74268

show subpopulations

Gnomad4 AFR

AF:

0.000314

Gnomad4 AMR

AF:

0.00360

Gnomad4 ASJ

AF:

0.0141

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00353

Gnomad4 FIN

AF:

0.000380

Gnomad4 NFE

AF:

0.00271

Gnomad4 OTH

AF:

0.00664

Alfa

AF:

0.00306

Hom.:

Bravo

AF:

0.00221

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00374

AC:

ExAC

AF:

0.00276

AC:

335

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.00404

EpiControl

AF:

0.00457

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Glycogen storage disease type III

Benign:3

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 15, 2021

Genome-Nilou Lab

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 06, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Benign:2

Oct 31, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

AGL: BP4, BS2 -

not specified

Benign:1

Mar 02, 2018

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. -

Inborn genetic diseases

Benign:1

Jan 08, 2022

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

AGL-related disorder

Benign:1

Aug 24, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.42

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.11

T;T;T;T;.

Eigen

Uncertain

0.24

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.97

D;.;.;.;D

M_CAP

Benign

0.035

MetaRNN

Benign

0.011

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.1

L;L;L;L;.

PrimateAI

Benign

0.46

PROVEAN

Benign

-2.2

N;N;N;N;N

REVEL

Benign

0.084

Sift

Benign

0.031

D;D;D;D;D

Sift4G

Uncertain

0.051

T;T;T;T;D

Polyphen

0.26

B;B;B;B;B

Vest4

0.28

MVP

0.53

MPC

0.060

ClinPred

0.030

GERP RS

5.8

Varity_R

0.46

gMVP

0.69

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over