9-99221766-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_033087.4(ALG2):c.129C>G(p.Arg43Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0199 in 1,598,624 control chromosomes in the GnomAD database, including 446 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.018 ( 60 hom., cov: 33)

Exomes 𝑓: 0.020 ( 386 hom. )

Consequence

ALG2
NM_033087.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.163

Publications

6 publications found

Variant links:

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

ALG2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.37).

BP6

Variant 9-99221766-G-C is Benign according to our data. Variant chr9-99221766-G-C is described in ClinVar as Benign. ClinVar VariationId is 262208.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.163 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0178 (2711/152320) while in subpopulation NFE AF = 0.0238 (1620/68016). AF 95% confidence interval is 0.0229. There are 60 homozygotes in GnomAd4. There are 1408 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 60 AR,Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALG2	NM_033087.4 link	c.129C>G	p.Arg43Arg	synonymous_variant	Exon 1 of 2	ENST00000476832.2	NP_149078.1
ALG2	NR_024532.2 link	n.177C>G		non_coding_transcript_exon_variant	Exon 1 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALG2	ENST00000476832.2 link	c.129C>G	p.Arg43Arg	synonymous_variant	Exon 1 of 2	1	NM_033087.4	ENSP00000417764.1
ALG2	ENST00000238477.5 link	n.129C>G		non_coding_transcript_exon_variant	Exon 1 of 3	2		ENSP00000432675.2

Frequencies

GnomAD3 genomes

AF:

0.0178

AC:

2711

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00321

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00733

Gnomad ASJ

AF:

0.00922

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.0101

Gnomad FIN

AF:

0.0687

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0238

Gnomad OTH

AF:

0.0148

GnomAD2 exomes

AF:

0.0176

AC:

3946

AN:

224496

AF XY:

0.0178

show subpopulations

Gnomad AFR exome

AF:

0.00263

Gnomad AMR exome

AF:

0.00610

Gnomad ASJ exome

AF:

0.00919

Gnomad EAS exome

AF:

0.000114

Gnomad FIN exome

AF:

0.0685

Gnomad NFE exome

AF:

0.0233

Gnomad OTH exome

AF:

0.0170

GnomAD4 exome

AF:

0.0201

AC:

29084

AN:

1446304

Hom.:

386

Cov.:

AF XY:

0.0199

AC XY:

14315

AN XY:

720032

show subpopulations

African (AFR)

AF:

0.00221

AC:

AN:

33426

American (AMR)

AF:

0.00703

AC:

314

AN:

44676

Ashkenazi Jewish (ASJ)

AF:

0.00844

AC:

220

AN:

26078

East Asian (EAS)

AF:

0.000101

AC:

AN:

39668

South Asian (SAS)

AF:

0.0104

AC:

893

AN:

86224

European-Finnish (FIN)

AF:

0.0646

AC:

2512

AN:

38872

Middle Eastern (MID)

AF:

0.00563

AC:

AN:

5680

European-Non Finnish (NFE)

AF:

0.0217

AC:

24085

AN:

1111484

Other (OTH)

AF:

0.0158

AC:

950

AN:

60196

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

1968

3935

5903

7870

9838

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

838

1676

2514

3352

4190

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0178

AC:

2711

AN:

152320

Hom.:

Cov.:

AF XY:

0.0189

AC XY:

1408

AN XY:

74496

show subpopulations

African (AFR)

AF:

0.00320

AC:

133

AN:

41584

American (AMR)

AF:

0.00732

AC:

112

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00922

AC:

AN:

3472

East Asian (EAS)

AF:

0.000386

AC:

AN:

5178

South Asian (SAS)

AF:

0.00995

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0687

AC:

729

AN:

10616

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0238

AC:

1620

AN:

68016

Other (OTH)

AF:

0.0147

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

139

277

416

554

693

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

150

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0197

Hom.:

Bravo

AF:

0.0122

Asia WGS

AF:

0.00462

AC:

AN:

3478

EpiCase

AF:

0.0205

EpiControl

AF:

0.0197

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Feb 17, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.37

CADD

Benign

(source)

DANN

Benign

0.84

PhyloP100

-0.16

PromoterAI

0.097

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over