rs2230305

Variant names:

• chr1-99861627-T-C
• rs2230305
• NM_000642.3:c.207T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000028.3(AGL):​c.207T>C​(p.Asn69Asn) 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 NM_000028.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.572
• Publications: 6 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 -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 VariationId is 256726.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 33 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000028.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGL	NM_000642.3	MANE Select	c.207T>C	p.Asn69Asn	synonymous	Exon 3 of 34	NP_000633.2
	AGL	NM_000028.3		c.207T>C	p.Asn69Asn	synonymous	Exon 3 of 34	NP_000019.2
	AGL	NM_000643.3		c.207T>C	p.Asn69Asn	synonymous	Exon 3 of 34	NP_000634.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGL	ENST00000361915.8	TSL:1 MANE Select	c.207T>C	p.Asn69Asn	synonymous	Exon 3 of 34	ENSP00000355106.3
	AGL	ENST00000294724.8	TSL:1	c.207T>C	p.Asn69Asn	synonymous	Exon 3 of 34	ENSP00000294724.4
	AGL	ENST00000370163.7	TSL:1	c.207T>C	p.Asn69Asn	synonymous	Exon 3 of 34	ENSP00000359182.3

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

GnomAD2 exomes AF: 0.0161 AC: 4043 AN: 251204 AF XY: 0.0160

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 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

African (AFR) AF: 0.00409 AC: 137 AN: 33456

American (AMR) AF: 0.00850 AC: 380 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0423 AC: 1104 AN: 26126

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39632

South Asian (SAS) AF: 0.00417 AC: 360 AN: 86252

European-Finnish (FIN) AF: 0.0383 AC: 2044 AN: 53416

Middle Eastern (MID) AF: 0.0470 AC: 271 AN: 5762

European-Non Finnish (NFE) AF: 0.0159 AC: 17648 AN: 1111748

Other (OTH) AF: 0.0177 AC: 1071 AN: 60382

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

African (AFR) AF: 0.00332 AC: 138 AN: 41532

American (AMR) AF: 0.0175 AC: 268 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0398 AC: 138 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00394 AC: 19 AN: 4818

European-Finnish (FIN) AF: 0.0393 AC: 416 AN: 10576

Middle Eastern (MID) AF: 0.0884 AC: 26 AN: 294

European-Non Finnish (NFE) AF: 0.0185 AC: 1258 AN: 68002

Other (OTH) AF: 0.0218 AC: 46 AN: 2110

Alfa AF: 0.0174 Hom.: 60

Bravo AF: 0.0128

Asia WGS AF: 0.00462 AC: 17 AN: 3478

EpiCase AF: 0.0194

EpiControl AF: 0.0187

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Glycogen storage disease type III (4)
-	-	3	not provided (3)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	5.3
DANN	Benign	0.65
PhyloP100		0.57
Mutation Taster		=100/0	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: rs2230305; hg19: chr1-100327183;