rs146770430

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_033087.4(ALG2):c.475A>G(p.Ile159Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000809 in 1,614,172 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00060 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00083 ( 3 hom. )

Consequence

ALG2
NM_033087.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:7

Conservation

PhyloP100: 1.69

Publications

7 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.015303463).

BP6

Variant 9-99218710-T-C is Benign according to our data. Variant chr9-99218710-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 390397.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000604 (92/152286) while in subpopulation EAS AF = 0.000771 (4/5190). AF 95% confidence interval is 0.000304. There are 1 homozygotes in GnomAd4. There are 46 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 3 AR,Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALG2	NM_033087.4 link	c.475A>G	p.Ile159Val	missense_variant	Exon 2 of 2	ENST00000476832.2	NP_149078.1	Q9H553-1A0A024R184
ALG2	XM_047423996.1 link	c.196A>G	p.Ile66Val	missense_variant	Exon 2 of 2		XP_047279952.1
ALG2	NR_024532.2 link	n.682A>G		non_coding_transcript_exon_variant	Exon 3 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ALG2	ENST00000476832.2 link	c.475A>G	p.Ile159Val	missense_variant	Exon 2 of 2	1	NM_033087.4	ENSP00000417764.1	Q9H553-1
ALG2	ENST00000319033.7 link	c.196A>G	p.Ile66Val	missense_variant	Exon 2 of 2	1		ENSP00000326609.6	Q9H553-2
ALG2	ENST00000238477.5 link	n.*217A>G		non_coding_transcript_exon_variant	Exon 3 of 3	2		ENSP00000432675.2	A0A0A0MTE0
ALG2	ENST00000238477.5 link	n.*217A>G		3_prime_UTR_variant	Exon 3 of 3	2		ENSP00000432675.2	A0A0A0MTE0

Frequencies

GnomAD3 genomes

AF:

0.000605

AC:

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000410

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000524

Gnomad ASJ

AF:

0.00749

Gnomad EAS

AF:

0.000769

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000426

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.000720

AC:

181

AN:

251480

AF XY:

0.000773

show subpopulations

Gnomad AFR exome

AF:

0.000554

Gnomad AMR exome

AF:

0.000173

Gnomad ASJ exome

AF:

0.00694

Gnomad EAS exome

AF:

0.000326

Gnomad FIN exome

AF:

0.0000924

Gnomad NFE exome

AF:

0.000527

Gnomad OTH exome

AF:

0.00277

GnomAD4 exome

AF:

0.000830

AC:

1214

AN:

1461886

Hom.:

Cov.:

AF XY:

0.000851

AC XY:

619

AN XY:

727244

show subpopulations

African (AFR)

AF:

0.000657

AC:

AN:

33480

American (AMR)

AF:

0.000291

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00681

AC:

178

AN:

26136

East Asian (EAS)

AF:

0.00416

AC:

165

AN:

39700

South Asian (SAS)

AF:

0.000452

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000936

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00451

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000613

AC:

682

AN:

1112006

Other (OTH)

AF:

0.00139

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

161

242

322

403

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

102

136

170

<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:

0.000604

AC:

AN:

152286

Hom.:

Cov.:

AF XY:

0.000618

AC XY:

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.000409

AC:

AN:

41564

American (AMR)

AF:

0.000523

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00749

AC:

AN:

3470

East Asian (EAS)

AF:

0.000771

AC:

AN:

5190

South Asian (SAS)

AF:

0.000208

AC:

AN:

4810

European-Finnish (FIN)

AF:

0.0000941

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000426

AC:

AN:

68016

Other (OTH)

AF:

0.00189

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00136

Hom.:

Bravo

AF:

0.000672

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000601

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000709

EpiControl

AF:

0.00136

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:4

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ALG2: BP4 -

May 02, 2018

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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

Uncertain:1Benign:1

Jan 08, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

ALG2-related disorder

Benign:1

Mar 23, 2020

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

See cases

Benign:1

Apr 08, 2020

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ACMG classification criteria: BP1, BP4 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.39

CADD

Benign

(source)

DANN

Benign

0.67

DEOGEN2

Benign

0.18

T;.

Eigen

Benign

-0.59

Eigen_PC

Benign

-0.60

FATHMM_MKL

Benign

0.70

LIST_S2

Benign

0.76

T;T

M_CAP

Benign

0.026

MetaRNN

Benign

0.015

T;T

MetaSVM

Benign

-0.83

MutationAssessor

Uncertain

2.2

M;.

PhyloP100

1.7

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.82

N;N

REVEL

Benign

0.11

Sift

Benign

0.12

T;T

Sift4G

Benign

0.18

T;T

Polyphen

0.090

B;B

Vest4

0.12

MVP

0.50

MPC

0.18

ClinPred

0.0075

GERP RS

1.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.097

gMVP

0.71

Mutation Taster

=89/11

polymorphism

(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