chr1-99884693-C-G

Position:

• chr1-99884693-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000642.3(AGL):​c.2671C>G​(p.Pro891Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,580 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: AGL NM_000642.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.04

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18861157).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AGL	NM_000642.3	c.2671C>G	p.Pro891Ala	missense_variant	20/34	ENST00000361915.8	NP_000633.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AGL	ENST00000361915.8	c.2671C>G	p.Pro891Ala	missense_variant	20/34	1	NM_000642.3	ENSP00000355106	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251006 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135648

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461580 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727080

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.094	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Benign	0.056	T;T;T;T;.
Eigen	Benign	-0.21
Eigen_PC	Benign	0.024
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.89	D;.;.;.;D
M_CAP	Benign	0.0089	T
MetaRNN	Benign	0.19	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.0	M;M;M;M;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.99	N;N;N;N;N
REVEL	Benign	0.094
Sift	Benign	0.14	T;T;T;T;T
Sift4G	Benign	0.78	T;T;T;T;T
Polyphen		0.073	B;B;B;B;B
Vest4		0.51
MutPred		0.38		Gain of catalytic residue at P891 (P = 0.0398);Gain of catalytic residue at P891 (P = 0.0398);Gain of catalytic residue at P891 (P = 0.0398);Gain of catalytic residue at P891 (P = 0.0398);.;
MVP		0.49
MPC		0.045
ClinPred		0.17	T
GERP RS		5.7
Varity_R		0.15
gMVP		0.57

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: rs777738895; hg19: chr1-100350249;