rs757347826

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The ENST00000361915.8(AGL):​c.766C>T​(p.Arg256Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000899 in 1,613,792 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R256H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000090 ( 0 hom. )

Consequence

AGL
ENST00000361915.8 missense

Scores

1
7
11

Clinical Significance

Uncertain significance criteria provided, single submitter U:2

Conservation

PhyloP100: 6.05
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.35592198).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
AGLNM_000642.3 linkuse as main transcriptc.766C>T p.Arg256Cys missense_variant 6/34 ENST00000361915.8 NP_000633.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
AGLENST00000361915.8 linkuse as main transcriptc.766C>T p.Arg256Cys missense_variant 6/341 NM_000642.3 ENSP00000355106 P1P35573-1

Frequencies

GnomAD3 genomes
AF:
0.0000855
AC:
13
AN:
152068
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000724
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000656
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000132
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000875
AC:
22
AN:
251312
Hom.:
0
AF XY:
0.0000957
AC XY:
13
AN XY:
135818
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000653
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000167
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.0000903
AC:
132
AN:
1461724
Hom.:
0
Cov.:
32
AF XY:
0.0000798
AC XY:
58
AN XY:
727178
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000232
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000113
Gnomad4 OTH exome
AF:
0.0000662
GnomAD4 genome
AF:
0.0000855
AC:
13
AN:
152068
Hom.:
0
Cov.:
32
AF XY:
0.000121
AC XY:
9
AN XY:
74274
show subpopulations
Gnomad4 AFR
AF:
0.0000724
Gnomad4 AMR
AF:
0.0000656
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000132
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000564
Hom.:
0
Bravo
AF:
0.0000604
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000259
AC:
1
ExAC
AF:
0.0000659
AC:
8
EpiCase
AF:
0.000218
EpiControl
AF:
0.000237

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Glycogen storage disease type III Uncertain:2
Uncertain significance, no assertion criteria providedclinical testingNatera, Inc.Oct 28, 2019- -
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJun 30, 2022This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 256 of the AGL protein (p.Arg256Cys). This variant is present in population databases (rs757347826, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with AGL-related conditions. ClinVar contains an entry for this variant (Variation ID: 581236). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.088
BayesDel_addAF
Benign
-0.12
T
BayesDel_noAF
Benign
-0.15
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.21
T;T;T;T;.
Eigen
Benign
0.14
Eigen_PC
Uncertain
0.27
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.93
D;.;.;.;D
M_CAP
Benign
0.063
D
MetaRNN
Benign
0.36
T;T;T;T;T
MetaSVM
Uncertain
-0.10
T
MutationAssessor
Benign
1.0
L;L;L;L;.
MutationTaster
Benign
1.0
D;D;D;D;D;D;D
PrimateAI
Benign
0.32
T
PROVEAN
Uncertain
-3.2
D;D;D;D;D
REVEL
Uncertain
0.47
Sift
Uncertain
0.0050
D;D;D;D;D
Sift4G
Benign
0.16
T;T;T;T;T
Polyphen
0.62
P;P;P;P;P
Vest4
0.28
MutPred
0.55
Loss of MoRF binding (P = 0.0027);Loss of MoRF binding (P = 0.0027);Loss of MoRF binding (P = 0.0027);Loss of MoRF binding (P = 0.0027);.;
MVP
0.92
MPC
0.051
ClinPred
0.17
T
GERP RS
5.4
Varity_R
0.26
gMVP
0.74

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

LitVar

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

Other links and lift over

dbSNP: rs757347826; hg19: chr1-100336057; COSMIC: COSV54048566; COSMIC: COSV54048566; API