rs201959100

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_033087.4(ALG2):c.167C>T(p.Pro56Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000342 in 1,598,192 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P56P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00060 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00032 ( 3 hom. )

Consequence

ALG2
NM_033087.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 8.69

Publications

5 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):

ALG2-congenital disorder of glycosylation
Inheritance: AR, Unknown Classification: STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: ClinGen, G2P, Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
congenital myasthenic syndrome 14
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
congenital myasthenic syndromes with glycosylation defect
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ALG2 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_033087.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.013409823).

BP6

Variant 9-99221728-G-A is Benign according to our data. Variant chr9-99221728-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 382799.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000597 (91/152354) while in subpopulation EAS AF = 0.0104 (54/5190). AF 95% confidence interval is 0.00819. There are 1 homozygotes in GnomAd4. There are 50 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 3 Unknown,AR gene

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.167C>T	p.Pro56Leu	missense	Exon 1 of 2	NP_149078.1	Q9H553-1
	ALG2	NR_024532.2		n.215C>T		non_coding_transcript_exon	Exon 1 of 3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ALG2	ENST00000476832.2	TSL:1 MANE Select	c.167C>T	p.Pro56Leu	missense	Exon 1 of 2	ENSP00000417764.1	Q9H553-1
ALG2	ENST00000906837.1		c.167C>T	p.Pro56Leu	missense	Exon 1 of 2	ENSP00000576896.1
ALG2	ENST00000238477.5	TSL:2	n.167C>T		non_coding_transcript_exon	Exon 1 of 3	ENSP00000432675.2	A0A0A0MTE0

Frequencies

GnomAD3 genomes

AF:

0.000585

AC:

AN:

152236

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000314

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0100

Gnomad SAS

AF:

0.00393

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000955

GnomAD2 exomes

AF:

0.000930

AC:

206

AN:

221450

AF XY:

0.000826

show subpopulations

Gnomad AFR exome

AF:

0.000443

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00947

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00142

GnomAD4 exome

AF:

0.000315

AC:

456

AN:

1445838

Hom.:

Cov.:

AF XY:

0.000340

AC XY:

245

AN XY:

719758

show subpopulations

African (AFR)

AF:

0.000180

AC:

AN:

33380

American (AMR)

AF:

0.0000448

AC:

AN:

44630

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26062

East Asian (EAS)

AF:

0.00426

AC:

169

AN:

39646

South Asian (SAS)

AF:

0.00166

AC:

143

AN:

86094

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39080

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5648

European-Non Finnish (NFE)

AF:

0.00000990

AC:

AN:

1111182

Other (OTH)

AF:

0.00208

AC:

125

AN:

60116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

103

137

171

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.000597

AC:

AN:

152354

Hom.:

Cov.:

AF XY:

0.000671

AC XY:

AN XY:

74508

show subpopulations

African (AFR)

AF:

0.000313

AC:

AN:

41588

American (AMR)

AF:

0.000131

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.0104

AC:

AN:

5190

South Asian (SAS)

AF:

0.00393

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68020

Other (OTH)

AF:

0.000945

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.517

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:

0.000830

Hom.:

Bravo

AF:

0.000325

Asia WGS

AF:

0.0250

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

ALG2-congenital disorder of glycosylation;C4015597:Congenital myasthenic syndrome 14 (2)

not specified (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.084

BayesDel_noAF

Uncertain

0.11

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.58

Eigen

Pathogenic

0.69

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.96

MetaRNN

Benign

0.013

MetaSVM

Uncertain

0.094

MutationAssessor

Uncertain

2.4

PhyloP100

8.7

PrimateAI

Uncertain

0.75

PROVEAN

Pathogenic

-6.6

REVEL

Pathogenic

0.68

Sift

Benign

0.036

Sift4G

Benign

0.10

PromoterAI

0.0073

Neutral

(source)

Varity_R

0.43

gMVP

0.71

Mutation Taster

=35/65

disease causing

(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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over