rs749075109

Positions:

• chr1-99881359-G-A
• chr1-99881359-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000642.3(AGL):​c.2069G>A​(p.Gly690Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 31)
• Consequence: AGL NM_000642.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.98

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AGL	NM_000642.3	c.2069G>A	p.Gly690Asp	missense_variant	16/34	ENST00000361915.8	NP_000633.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AGL	ENST00000361915.8	c.2069G>A	p.Gly690Asp	missense_variant	16/34	1	NM_000642.3	ENSP00000355106	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	20
DANN	Benign	0.74
DEOGEN2	Benign	0.12	T;T;T;T;.
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.39
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.70	T;.;.;.;T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.15	T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.90	L;L;L;L;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.42	N;N;N;N;N
REVEL	Benign	0.097
Sift	Benign	0.49	T;T;T;T;T
Sift4G	Benign	0.62	T;T;T;T;T
Polyphen		0.0	B;B;B;B;B
Vest4		0.23
MutPred		0.25		Gain of solvent accessibility (P = 0.0638);Gain of solvent accessibility (P = 0.0638);Gain of solvent accessibility (P = 0.0638);Gain of solvent accessibility (P = 0.0638);.;
MVP		0.79
MPC		0.049
ClinPred		0.037	T
GERP RS		2.6
Varity_R		0.045
gMVP		0.55

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.25		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.25		Position offset: 36

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs749075109; hg19: chr1-100346915;