rs730880304

Positions:

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

Variant summary

Our verdict is Uncertain significance. Variant got 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

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 Uncertain_significance. Variant got 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 id is 2700.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALG2	NM_033087.4	c.393G>T	p.Lys131Asn	missense_variant	2/2	ENST00000476832.2	NP_149078.1
ALG2	XM_047423996.1	c.114G>T	p.Lys38Asn	missense_variant	2/2		XP_047279952.1
ALG2	NR_024532.2	n.600G>T		non_coding_transcript_exon_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALG2	ENST00000476832.2	c.393G>T	p.Lys131Asn	missense_variant	2/2	1	NM_033087.4	ENSP00000417764.1
ALG2	ENST00000319033.7	c.114G>T	p.Lys38Asn	missense_variant	2/2	1		ENSP00000326609.6
ALG2	ENST00000238477.5	n.*135G>T		non_coding_transcript_exon_variant	3/3	2		ENSP00000432675.2
ALG2	ENST00000238477.5	n.*135G>T		3_prime_UTR_variant	3/3	2		ENSP00000432675.2

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

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: 0.0000203

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

ALG2-congenital disorder of glycosylation Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 20, 2003

- -

Computational scores

Source: dbNSFP v4.3

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;D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.90	D;D
MetaSVM	Uncertain	-0.11	T
MutationAssessor	Uncertain	2.4	M;.
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-1.2	N;N
REVEL	Uncertain	0.45
Sift	Benign	0.20	T;T
Sift4G	Benign	0.46	T;T
Polyphen		0.20	B;P
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs730880304; hg19: chr9-101981074;