NM_024079.5:c.665A>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_024079.5(ALG8):c.665A>G(p.Asn222Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.216 in 1,613,832 control chromosomes in the GnomAD database, including 39,483 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.18 ( 2910 hom., cov: 33)

Exomes 𝑓: 0.22 ( 36573 hom. )

Consequence

ALG8
NM_024079.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 0.542

Publications

36 publications found

Variant links:

Genes affected

ALG8 (HGNC:23161): (ALG8 alpha-1,3-glucosyltransferase) This gene encodes a member of the ALG6/ALG8 glucosyltransferase family. The encoded protein catalyzes the addition of the second glucose residue to the lipid-linked oligosaccharide precursor for N-linked glycosylation of proteins. Mutations in this gene have been associated with congenital disorder of glycosylation type Ih (CDG-Ih). Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

ALG8 Gene-Disease associations (from GenCC):

ALG8-congenital disorder of glycosylation
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: PanelApp Australia, G2P, Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
polycystic liver disease 3 with or without kidney cysts
Inheritance: AD Classification: STRONG, LIMITED Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp

ALG8 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0013854206).

BP6

Variant 11-78114274-T-C is Benign according to our data. Variant chr11-78114274-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 96092.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.23 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALG8	NM_024079.5 link	c.665A>G	p.Asn222Ser	missense_variant	Exon 6 of 13	ENST00000299626.10	NP_076984.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALG8	ENST00000299626.10 link	c.665A>G	p.Asn222Ser	missense_variant	Exon 6 of 13	1	NM_024079.5	ENSP00000299626.5

Frequencies

GnomAD3 genomes

AF:

0.178

AC:

27115

AN:

152124

Hom.:

2909

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0620

Gnomad AMI

AF:

0.160

Gnomad AMR

AF:

0.231

Gnomad ASJ

AF:

0.300

Gnomad EAS

AF:

0.0927

Gnomad SAS

AF:

0.206

Gnomad FIN

AF:

0.191

Gnomad MID

AF:

0.307

Gnomad NFE

AF:

0.233

Gnomad OTH

AF:

0.197

GnomAD2 exomes

AF:

0.202

AC:

50661

AN:

250942

AF XY:

0.206

show subpopulations

Gnomad AFR exome

AF:

0.0602

Gnomad AMR exome

AF:

0.213

Gnomad ASJ exome

AF:

0.306

Gnomad EAS exome

AF:

0.100

Gnomad FIN exome

AF:

0.180

Gnomad NFE exome

AF:

0.228

Gnomad OTH exome

AF:

0.215

GnomAD4 exome

AF:

0.220

AC:

321515

AN:

1461590

Hom.:

36573

Cov.:

AF XY:

0.221

AC XY:

160373

AN XY:

727118

show subpopulations

African (AFR)

AF:

0.0585

AC:

1960

AN:

33478

American (AMR)

AF:

0.216

AC:

9660

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.305

AC:

7961

AN:

26128

East Asian (EAS)

AF:

0.0839

AC:

3328

AN:

39682

South Asian (SAS)

AF:

0.206

AC:

17743

AN:

86252

European-Finnish (FIN)

AF:

0.184

AC:

9804

AN:

53354

Middle Eastern (MID)

AF:

0.261

AC:

1504

AN:

5766

European-Non Finnish (NFE)

AF:

0.231

AC:

256626

AN:

1111826

Other (OTH)

AF:

0.214

AC:

12929

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

13866

27732

41598

55464

69330

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8678

17356

26034

34712

43390

<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:

0.178

AC:

27122

AN:

152242

Hom.:

2910

Cov.:

AF XY:

0.178

AC XY:

13213

AN XY:

74420

show subpopulations

African (AFR)

AF:

0.0618

AC:

2570

AN:

41584

American (AMR)

AF:

0.232

AC:

3543

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.300

AC:

1041

AN:

3470

East Asian (EAS)

AF:

0.0933

AC:

484

AN:

5190

South Asian (SAS)

AF:

0.207

AC:

999

AN:

4824

European-Finnish (FIN)

AF:

0.191

AC:

2019

AN:

10584

Middle Eastern (MID)

AF:

0.289

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.233

AC:

15823

AN:

67996

Other (OTH)

AF:

0.195

AC:

412

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1117

2234

3351

4468

5585

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

296

592

888

1184

1480

<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:

0.215

Hom.:

12919

Bravo

AF:

0.175

TwinsUK

AF:

0.228

AC:

846

ALSPAC

AF:

0.246

AC:

948

ESP6500AA

AF:

0.0739

AC:

325

ESP6500EA

AF:

0.229

AC:

1967

ExAC

AF:

0.199

AC:

24110

Asia WGS

AF:

0.139

AC:

482

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

ALG8 congenital disorder of glycosylation

Benign:5

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 14, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 31, 2018

SIB Swiss Institute of Bioinformatics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:curation

This variant is interpreted as a Benign - Stand Alone, for Congenital disorder of glycosylation, type Ih, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: BA1 => Allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:3

Oct 04, 2012

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Jul 05, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.054

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.37

CADD

Benign

(source)

DANN

Benign

0.33

DEOGEN2

Benign

0.11

T;.;.;T;T;.;.;.

Eigen

Benign

-0.60

Eigen_PC

Benign

-0.44

FATHMM_MKL

Uncertain

0.85

LIST_S2

Uncertain

0.87

D;.;D;D;D;D;D;T

MetaRNN

Benign

0.0014

T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.58

N;N;N;.;.;.;.;.

PhyloP100

0.54

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.42

N;N;.;N;N;N;N;N

REVEL

Benign

0.14

Sift

Benign

0.85

T;T;.;T;T;T;T;T

Sift4G

Benign

0.65

T;T;T;.;.;.;.;.

Polyphen

0.0

B;.;.;.;.;.;.;.

Vest4

0.054

MPC

0.12

ClinPred

0.0056

GERP RS

1.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.014

gMVP

0.081

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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