rs34714252

Variant names:

• chr1-99891292-C-G
• rs34714252
• NM_000642.3:c.2885C>G

Your query was ambiguous. Multiple possible variants found:

• chr1-99891292-C-G
• chr1-99891292-C-T

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.2885C>G​(p.Ser962Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00253 in 1,613,666 control chromosomes in the GnomAD database, including 90 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S962T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.013 (51 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (39 hom.)
• Consequence: AGL NM_000642.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 2.71
• Publications: 4 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: Orphanet, Myriad Women’s Health, Genomics England PanelApp, ClinGen, PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics, Laboratory for Molecular Medicine, G2P

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008669406).
• BP6: Variant 1-99891292-C-G is Benign according to our data. Variant chr1-99891292-C-G is described in ClinVar as Benign. ClinVar VariationId is 256732.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 = 0.0133 (2028/152158) while in subpopulation AFR AF = 0.046 (1912/41530). AF 95% confidence interval is 0.0443. There are 51 homozygotes in GnomAd4. There are 955 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 51 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.2885C>G	p.Ser962Cys	missense	Exon 22 of 34	NP_000633.2
	AGL	NM_000028.3		c.2885C>G	p.Ser962Cys	missense	Exon 22 of 34	NP_000019.2
	AGL	NM_000643.3		c.2885C>G	p.Ser962Cys	missense	Exon 22 of 34	NP_000634.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGL	ENST00000361915.8	TSL:1 MANE Select	c.2885C>G	p.Ser962Cys	missense	Exon 22 of 34	ENSP00000355106.3
	AGL	ENST00000294724.8	TSL:1	c.2885C>G	p.Ser962Cys	missense	Exon 22 of 34	ENSP00000294724.4
	AGL	ENST00000370163.7	TSL:1	c.2885C>G	p.Ser962Cys	missense	Exon 22 of 34	ENSP00000359182.3

Frequencies

GnomAD3 genomes AF: 0.0133 AC: 2025 AN: 152040 Hom.: 50 Cov.: 32

Gnomad AFR AF: 0.0461

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00564

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00909

GnomAD2 exomes AF: 0.00354 AC: 888 AN: 251194 AF XY: 0.00263

Gnomad AFR exome AF: 0.0475

Gnomad AMR exome AF: 0.00246

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000123

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.00141 AC: 2054 AN: 1461508 Hom.: 39 Cov.: 32 AF XY: 0.00121 AC XY: 877 AN XY: 727044

African (AFR) AF: 0.0505 AC: 1690 AN: 33466

American (AMR) AF: 0.00246 AC: 110 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.000128 AC: 11 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.00226 AC: 13 AN: 5760

European-Non Finnish (NFE) AF: 0.0000765 AC: 85 AN: 1111758

Other (OTH) AF: 0.00238 AC: 144 AN: 60388

GnomAD4 genome AF: 0.0133 AC: 2028 AN: 152158 Hom.: 51 Cov.: 32 AF XY: 0.0128 AC XY: 955 AN XY: 74392

African (AFR) AF: 0.0460 AC: 1912 AN: 41530

American (AMR) AF: 0.00563 AC: 86 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 67956

Other (OTH) AF: 0.00900 AC: 19 AN: 2112

Alfa AF: 0.00368 Hom.: 1

Bravo AF: 0.0142

ESP6500AA AF: 0.0486 AC: 214

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00436 AC: 529

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000237

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)
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Benign	0.20	T
Eigen	Benign	-0.14
Eigen_PC	Benign	0.054
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.81	T
MetaRNN	Benign	0.0087	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L
PhyloP100		2.7
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-3.1	D
REVEL	Benign	0.048
Sift	Uncertain	0.010	D
Sift4G	Benign	0.069	T
Polyphen		0.0010	B
Vest4		0.34
MVP		0.55
MPC		0.041
ClinPred		0.024	T
GERP RS		4.8
Varity_R		0.29
gMVP		0.36
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: rs34714252; hg19: chr1-100356848;