NM_000642.3:c.2546+10T>C

Variant names:

• chr1-99884461-T-C
• rs74551473
• NM_000642.3:c.2546+10T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000642.3(AGL):​c.2546+10T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000343 in 1,605,570 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0020 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00017 (2 hom.)
• Consequence: AGL NM_000642.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.190
• Publications: 0 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=-0.84).
• BP6: Variant 1-99884461-T-C is Benign according to our data. Variant chr1-99884461-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 256728.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00198 (301/152344) while in subpopulation AFR AF = 0.0069 (287/41580). AF 95% confidence interval is 0.00625. There are 1 homozygotes in GnomAd4. There are 142 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000642.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGL	NM_000642.3	MANE Select	c.2546+10T>C		intron	N/A	NP_000633.2
	AGL	NM_000028.3		c.2546+10T>C		intron	N/A	NP_000019.2
	AGL	NM_000643.3		c.2546+10T>C		intron	N/A	NP_000634.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGL	ENST00000361915.8	TSL:1 MANE Select	c.2546+10T>C		intron	N/A	ENSP00000355106.3
	AGL	ENST00000294724.8	TSL:1	c.2546+10T>C		intron	N/A	ENSP00000294724.4
	AGL	ENST00000370163.7	TSL:1	c.2546+10T>C		intron	N/A	ENSP00000359182.3

Frequencies

GnomAD3 genomes AF: 0.00197 AC: 300 AN: 152226 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00690

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

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: 0.0000294

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.000491 AC: 121 AN: 246494 AF XY: 0.000366

Gnomad AFR exome AF: 0.00729

Gnomad AMR exome AF: 0.000234

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000167

GnomAD4 exome AF: 0.000172 AC: 250 AN: 1453226 Hom.: 2 Cov.: 30 AF XY: 0.000142 AC XY: 103 AN XY: 723272

African (AFR) AF: 0.00646 AC: 215 AN: 33282

American (AMR) AF: 0.000269 AC: 12 AN: 44542

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26070

East Asian (EAS) AF: 0.00 AC: 0 AN: 39572

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86030

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52958

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5744

European-Non Finnish (NFE) AF: 0.00000543 AC: 6 AN: 1104902

Other (OTH) AF: 0.000233 AC: 14 AN: 60126

GnomAD4 genome AF: 0.00198 AC: 301 AN: 152344 Hom.: 1 Cov.: 32 AF XY: 0.00191 AC XY: 142 AN XY: 74502

African (AFR) AF: 0.00690 AC: 287 AN: 41580

American (AMR) AF: 0.000588 AC: 9 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68022

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.000893 Hom.: 0

Bravo AF: 0.00223

Asia WGS AF: 0.000867 AC: 3 AN: 3476

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Glycogen storage disease type III (3)
-	-	2	not specified (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	4.0
DANN	Benign	0.60
PhyloP100		0.19
Mutation Taster		=100/0	polymorphism

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: rs74551473; hg19: chr1-100350017;