rs1554707637

Variant names:

• chr9-99218129-GG-TCA
• rs1554707637
• NM_033087.4:c.1055_1056delCCinsTGA

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

The NM_033087.4(ALG2):​c.1055_1056delCCinsTGA​(p.Ser352LeufsTer3) variant causes a frameshift, stop gained change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S352S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ALG2 NM_033087.4 frameshift, stop_gained
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:3
• Conservation: PhyloP100: 7.17
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• congenital myasthenic syndrome 14

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• ALG2-congenital disorder of glycosylation

  Inheritance: Unknown, AR Classification: STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen, G2P, Orphanet
• congenital myasthenic syndromes with glycosylation defect

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 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 0.157 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-99218129-GG-TCA is Pathogenic according to our data. Variant chr9-99218129-GG-TCA is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 464893.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033087.4. 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
	ALG2	NM_033087.4	MANE Select	c.1055_1056delCCinsTGA	p.Ser352LeufsTer3	frameshift stop_gained	Exon 2 of 2	NP_149078.1	Q9H553-1
	ALG2	NR_024532.2		n.1262_1263delCCinsTGA		non_coding_transcript_exon	Exon 3 of 3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALG2	ENST00000476832.2	TSL:1 MANE Select	c.1055_1056delCCinsTGA	p.Ser352LeufsTer3	frameshift stop_gained	Exon 2 of 2	ENSP00000417764.1	Q9H553-1
	ALG2	ENST00000319033.7	TSL:1	c.776_777delCCinsTGA	p.Ser259LeufsTer3	frameshift stop_gained	Exon 2 of 2	ENSP00000326609.6	Q9H553-2
	ALG2	ENST00000906837.1		c.908_909delCCinsTGA	p.Ser303LeufsTer3	frameshift stop_gained	Exon 2 of 2	ENSP00000576896.1

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	-	-	ALG2-congenital disorder of glycosylation (1)
-	1	-	ALG2-congenital disorder of glycosylation;C4015597:Congenital myasthenic syndrome 14 (1)
-	1	-	Inborn genetic diseases (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.2

Splicing

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

Other links and lift over

dbSNP: rs1554707637; hg19: chr9-101980411;