rs730882123

Variant names:

• chr9-99221671-AGCCAGTCCCC-CGGGGACT
• rs730882123
• NM_033087.4:c.214_224delGGGGACTGGCTinsAGTCCCCG

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PS1 PM2 PM4_Supporting PP5_Moderate

The NM_033087.4(ALG2):​c.214_224delGGGGACTGGCTinsAGTCCCCG​(p.Gly72_Leu75delinsSerProArg) variant causes a missense, conservative inframe deletion change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in Lovd.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ALG2 NM_033087.4 missense, conservative_inframe_deletion
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 6.78

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PS1: Transcript NM_033087.4 (ALG2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_033087.4. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 9-99221671-AGCCAGTCCCC-CGGGGACT is Pathogenic according to our data. Variant chr9-99221671-AGCCAGTCCCC-CGGGGACT is described in ClinVar as [Pathogenic]. Clinvar id is 183018.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALG2	NM_033087.4	c.214_224delGGGGACTGGCTinsAGTCCCCG	p.Gly72_Leu75delinsSerProArg	missense_variant, conservative_inframe_deletion		ENST00000476832.2	NP_149078.1
ALG2	NR_024532.2	n.262_272delGGGGACTGGCTinsAGTCCCCG		non_coding_transcript_exon_variant	Exon 1 of 3
ALG2	XM_047423996.1	c.-634_-624delGGGGACTGGCTinsAGTCCCCG		upstream_gene_variant			XP_047279952.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALG2	ENST00000476832.2	c.214_224delGGGGACTGGCTinsAGTCCCCG	p.Gly72_Leu75delinsSerProArg	missense_variant, conservative_inframe_deletion		1	NM_033087.4	ENSP00000417764.1
ALG2	ENST00000238477.5	n.214_224delGGGGACTGGCTinsAGTCCCCG		non_coding_transcript_exon_variant	Exon 1 of 3	2		ENSP00000432675.2

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Congenital myasthenic syndrome 14 Pathogenic:1

Apr 01, 2014

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:1

Nov 06, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP1_strong, PM2_moderate, PM3, PM4, PS4_moderate -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs730882123; hg19: chr9-101983953;