rs730880304

Variant names:

• chr9-99218792-C-A
• rs730880304
• NM_033087.4:c.393G>T

Your query was ambiguous. Multiple possible variants found:

• chr9-99218792-C-A
• chr9-99218792-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_033087.4(ALG2):​c.393G>T​(p.Lys131Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000000686 in 1,457,662 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: ALG2 NM_033087.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.86
• Publications: 2 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, MODERATE Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• ALG2-congenital disorder of glycosylation

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

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.897
• PP5: Variant 9-99218792-C-A is Pathogenic according to our data. Variant chr9-99218792-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 2700.Status of the report is no_assertion_criteria_provided, 0 stars.

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.393G>T	p.Lys131Asn	missense	Exon 2 of 2	NP_149078.1
	ALG2	NR_024532.2		n.600G>T		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.393G>T	p.Lys131Asn	missense	Exon 2 of 2	ENSP00000417764.1
	ALG2	ENST00000319033.7	TSL:1	c.114G>T	p.Lys38Asn	missense	Exon 2 of 2	ENSP00000326609.6
	ALG2	ENST00000906837.1		c.246G>T	p.Lys82Asn	missense	Exon 2 of 2	ENSP00000576896.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457662 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 725286

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.0000203 AC: 1 AN: 49256

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111984

Other (OTH) AF: 0.00 AC: 0 AN: 60364

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	ALG2-congenital disorder of glycosylation (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Uncertain	0.059	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.25	T
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Uncertain	-0.11	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		5.9
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-1.2	N
REVEL	Uncertain	0.45
Sift	Benign	0.20	T
Sift4G	Benign	0.46	T
Polyphen		0.20	B
Vest4		0.81
MutPred		0.81		Gain of sheet (P = 0.0085)
MVP		0.84
MPC		0.36
ClinPred		0.89	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.61
gMVP		0.92
Mutation Taster		=9/91	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.38		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.38		Position offset: -29

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

Other links and lift over

dbSNP: rs730880304; hg19: chr9-101981074;