rs387906281

Positions:

• chr9-99218144-AC-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_033087.4(ALG2):​c.1040delG​(p.Gly347fs) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000552 in 1,611,228 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000053 (0 hom.)
• Consequence: ALG2 NM_033087.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.50

Genes affected

ALG2 (HGNC:23159): (ALG2 alpha-1,3/1,6-mannosyltransferase) This gene encodes a member of the glycosyltransferase 1 family. The encoded protein acts as an alpha 1,3 mannosyltransferase, mannosylating Man(2)GlcNAc(2)-dolichol diphosphate and Man(1)GlcNAc(2)-dolichol diphosphate to form Man(3)GlcNAc(2)-dolichol diphosphate. Defects in this gene have been associated with congenital disorder of glycosylation type Ih (CDG-Ii). Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2008]

ALG2 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.169 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-99218144-AC-A is Pathogenic according to our data. Variant chr9-99218144-AC-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2699.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALG2	NM_033087.4	c.1040delG	p.Gly347fs	frameshift_variant	2/2	ENST00000476832.2	NP_149078.1
ALG2	XM_047423996.1	c.761delG	p.Gly254fs	frameshift_variant	2/2		XP_047279952.1
ALG2	NR_024532.2	n.1247delG		non_coding_transcript_exon_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALG2	ENST00000476832.2	c.1040delG	p.Gly347fs	frameshift_variant	2/2	1	NM_033087.4	ENSP00000417764.1
ALG2	ENST00000319033.7	c.761delG	p.Gly254fs	frameshift_variant	2/2	1		ENSP00000326609.6
ALG2	ENST00000238477.5	n.*782delG		non_coding_transcript_exon_variant	3/3	2		ENSP00000432675.2
ALG2	ENST00000238477.5	n.*782delG		3_prime_UTR_variant	3/3	2		ENSP00000432675.2

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152196 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000439 AC: 11 AN: 250348 Hom.: 0 AF XY: 0.0000444 AC XY: 6 AN XY: 135286

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: 0.0000972

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000535 AC: 78 AN: 1459032 Hom.: 0 Cov.: 31 AF XY: 0.0000483 AC XY: 35 AN XY: 725338

Gnomad4 AFR exome AF: 0.0000299

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: 0.0000187

Gnomad4 NFE exome AF: 0.0000658

Gnomad4 OTH exome AF: 0.0000498

GnomAD4 genome AF: 0.0000723 AC: 11 AN: 152196 Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3 AN XY: 74376

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000529

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

ALG2-congenital disorder of glycosylation Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 10, 2024	Variant summary: ALG2 c.1040delG (p.Gly347ValfsX27) results in a premature termination codon, predicted to cause a truncation of the encoded protein. The variant allele was found at a frequency of 4.4e-05 in 250348 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in ALG2 causing Congenital Disorder Of Glycosylation, Type 1i, allowing no conclusion about variant significance. c.1040delG has been reported in the literature in individuals affected with features of Congenital Disorder Of Glycosylation, Type 1i (Thiel_2003, Ehrstedt_2022). These publications report experimental evidence evaluating an impact on protein function, indicating that the variant results in a null allele. The following publications have been ascertained in the context of this evaluation (PMID: 12684507, 34980536). ClinVar contains an entry for this variant (Variation ID: 2699). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 20, 2003	- -

ALG2-congenital disorder of glycosylation;C4015597:Congenital myasthenic syndrome 14 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 20, 2022

ClinVar contains an entry for this variant (Variation ID: 2699). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this premature translational stop signal affects ALG2 function (PMID: 12684507). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. This premature translational stop signal has been observed in individuals with ALG2-related disease (PMID: 12684507; Invitae). This variant is present in population databases (rs387906281, gnomAD 0.01%). This sequence change creates a premature translational stop signal (p.Gly347Valfs*27) in the ALG2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 70 amino acid(s) of the ALG2 protein. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Sep 20, 2023

Published functional studies demonstrate a damaging effect, as the variant is a null allele that results in significantly reduced expression (Ehrstedt et al., 2022); Frameshift variant predicted to result in protein truncation as the last 70 amino acids are replaced with 26 different amino acids, although loss-of-function variants have not been reported downstream of this position in the protein; This variant is associated with the following publications: (PMID: 12684507, 34980536) -

Computational scores

Source: dbNSFP v4.3

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: rs387906281; hg19: chr9-101980426;