rs2230305

Positions:

• chr1-99861627-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The ENST00000361915.8(AGL):​c.207T>C​(p.Asn69=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0157 in 1,613,662 control chromosomes in the GnomAD database, including 249 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (33 hom., cov: 32)
  • Exomes 𝑓: 0.016 (216 hom.)
• Consequence: AGL ENST00000361915.8 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.572

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 1-99861627-T-C is Benign according to our data. Variant chr1-99861627-T-C is described in ClinVar as [Benign]. Clinvar id is 256726.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-99861627-T-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.572 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0152 (2309/152172) while in subpopulation NFE AF= 0.0185 (1258/68002). AF 95% confidence interval is 0.0176. There are 33 homozygotes in gnomad4. There are 1156 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 33 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AGL	NM_000642.3	c.207T>C	p.Asn69=	synonymous_variant	3/34	ENST00000361915.8	NP_000633.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AGL	ENST00000361915.8	c.207T>C	p.Asn69=	synonymous_variant	3/34	1	NM_000642.3	ENSP00000355106	P1

Frequencies

GnomAD3 genomes AF: 0.0152 AC: 2311 AN: 152054 Hom.: 33 Cov.: 32

Gnomad AFR AF: 0.00333

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0176

Gnomad ASJ AF: 0.0398

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00394

Gnomad FIN AF: 0.0393

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.0185

Gnomad OTH AF: 0.0220

GnomAD3 exomes AF: 0.0161 AC: 4043 AN: 251204 Hom.: 47 AF XY: 0.0160 AC XY: 2174 AN XY: 135808

Gnomad AFR exome AF: 0.00241

Gnomad AMR exome AF: 0.00772

Gnomad ASJ exome AF: 0.0415

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00369

Gnomad FIN exome AF: 0.0374

Gnomad NFE exome AF: 0.0198

Gnomad OTH exome AF: 0.0239

GnomAD4 exome AF: 0.0157 AC: 23016 AN: 1461490 Hom.: 216 Cov.: 32 AF XY: 0.0156 AC XY: 11377 AN XY: 727070

Gnomad4 AFR exome AF: 0.00409

Gnomad4 AMR exome AF: 0.00850

Gnomad4 ASJ exome AF: 0.0423

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00417

Gnomad4 FIN exome AF: 0.0383

Gnomad4 NFE exome AF: 0.0159

Gnomad4 OTH exome AF: 0.0177

GnomAD4 genome AF: 0.0152 AC: 2309 AN: 152172 Hom.: 33 Cov.: 32 AF XY: 0.0155 AC XY: 1156 AN XY: 74398

Gnomad4 AFR AF: 0.00332

Gnomad4 AMR AF: 0.0175

Gnomad4 ASJ AF: 0.0398

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00394

Gnomad4 FIN AF: 0.0393

Gnomad4 NFE AF: 0.0185

Gnomad4 OTH AF: 0.0218

Alfa AF: 0.0203 Hom.: 26

Bravo AF: 0.0128

Asia WGS AF: 0.00462 AC: 17 AN: 3478

EpiCase AF: 0.0194

EpiControl AF: 0.0187

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glycogen storage disease type III Benign:4

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 31, 2023	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 14, 2017	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 10, 2016	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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	5.3
DANN	Benign	0.65

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

Other links and lift over

dbSNP: rs2230305; hg19: chr1-100327183;