rs2307129

Variant names:

• chr1-99861470-C-T
• rs2307129
• ENST00000637337.1:n.261C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000637337.1(AGL):​n.261C>T variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.18 in 1,611,300 control chromosomes in the GnomAD database, including 28,789 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.24 (5046 hom., cov: 32)
  • Exomes 𝑓: 0.17 (23743 hom.)
• Consequence: AGL ENST00000637337.1 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.01
• Publications: 17 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 1-99861470-C-T is Benign according to our data. Variant chr1-99861470-C-T is described in ClinVar as [Benign]. Clinvar id is 256750.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.385 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGL	NM_000642.3	c.83-33C>T		intron_variant	Intron 2 of 33	ENST00000361915.8	NP_000633.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGL	ENST00000361915.8	c.83-33C>T		intron_variant	Intron 2 of 33	1	NM_000642.3	ENSP00000355106.3

Frequencies

GnomAD3 genomes AF: 0.235 AC: 35761 AN: 151892 Hom.: 5048 Cov.: 32

Gnomad AFR AF: 0.390

Gnomad AMI AF: 0.219

Gnomad AMR AF: 0.188

Gnomad ASJ AF: 0.247

Gnomad EAS AF: 0.119

Gnomad SAS AF: 0.195

Gnomad FIN AF: 0.195

Gnomad MID AF: 0.306

Gnomad NFE AF: 0.170

Gnomad OTH AF: 0.229

GnomAD2 exomes AF: 0.184 AC: 45917 AN: 249460 AF XY: 0.183

Gnomad AFR exome AF: 0.386

Gnomad AMR exome AF: 0.131

Gnomad ASJ exome AF: 0.254

Gnomad EAS exome AF: 0.122

Gnomad FIN exome AF: 0.192

Gnomad NFE exome AF: 0.171

Gnomad OTH exome AF: 0.197

GnomAD4 exome AF: 0.175 AC: 254822 AN: 1459290 Hom.: 23743 Cov.: 33 AF XY: 0.175 AC XY: 127188 AN XY: 725964

African (AFR) AF: 0.397 AC: 13241 AN: 33384

American (AMR) AF: 0.140 AC: 6229 AN: 44610

Ashkenazi Jewish (ASJ) AF: 0.247 AC: 6450 AN: 26090

East Asian (EAS) AF: 0.111 AC: 4395 AN: 39614

South Asian (SAS) AF: 0.189 AC: 16280 AN: 86026

European-Finnish (FIN) AF: 0.193 AC: 10307 AN: 53356

Middle Eastern (MID) AF: 0.297 AC: 1708 AN: 5744

European-Non Finnish (NFE) AF: 0.166 AC: 184664 AN: 1110182

Other (OTH) AF: 0.192 AC: 11548 AN: 60284

GnomAD4 genome AF: 0.235 AC: 35761 AN: 152010 Hom.: 5046 Cov.: 32 AF XY: 0.234 AC XY: 17424 AN XY: 74310

African (AFR) AF: 0.390 AC: 16140 AN: 41426

American (AMR) AF: 0.187 AC: 2856 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.247 AC: 855 AN: 3466

East Asian (EAS) AF: 0.119 AC: 617 AN: 5188

South Asian (SAS) AF: 0.194 AC: 937 AN: 4818

European-Finnish (FIN) AF: 0.195 AC: 2058 AN: 10554

Middle Eastern (MID) AF: 0.288 AC: 84 AN: 292

European-Non Finnish (NFE) AF: 0.170 AC: 11539 AN: 67972

Other (OTH) AF: 0.225 AC: 475 AN: 2108

Alfa AF: 0.192 Hom.: 13835

Bravo AF: 0.238

Asia WGS AF: 0.165 AC: 573 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 02, 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:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Glycogen storage disease type III Benign:1

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	4.1
DANN	Benign	0.62
PhyloP100		-1.0
Mutation Taster		=300/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2307129; hg19: chr1-100327026; COSMIC: COSV54053030;