rs56393253

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBS1_Supporting

The NM_033087.4(ALG2):c.1132C>T(p.Arg378Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000573 in 1,614,126 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R378H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00051 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00058 ( 2 hom. )

Consequence

ALG2
NM_033087.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 4.40

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.07675636).

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000512 (78/152276) while in subpopulation AFR AF= 0.000914 (38/41560). AF 95% confidence interval is 0.000684. There are 0 homozygotes in gnomad4. There are 35 alleles in male gnomad4 subpopulation. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
ALG2	NM_033087.4 linkuse as main transcript	c.1132C>T	p.Arg378Cys	missense_variant	2/2	ENST00000476832.2
ALG2	XM_047423996.1 linkuse as main transcript	c.853C>T	p.Arg285Cys	missense_variant	2/2
ALG2	NR_024532.2 linkuse as main transcript	n.1339C>T		non_coding_transcript_exon_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALG2	ENST00000476832.2 linkuse as main transcript	c.1132C>T	p.Arg378Cys	missense_variant	2/2	1	NM_033087.4	P1	Q9H553-1
ALG2	ENST00000319033.7 linkuse as main transcript	c.853C>T	p.Arg285Cys	missense_variant	2/2	1			Q9H553-2
ALG2	ENST00000238477.5 linkuse as main transcript	c.*874C>T		3_prime_UTR_variant, NMD_transcript_variant	3/3	2

Frequencies

GnomAD3 genomes

AF:

0.000513

AC:

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000917

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000470

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000346

AC:

AN:

251412

Hom.:

AF XY:

0.000309

AC XY:

AN XY:

135884

show subpopulations

Gnomad AFR exome

AF:

0.00111

Gnomad AMR exome

AF:

0.000376

Gnomad ASJ exome

AF:

0.000198

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000413

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000579

AC:

847

AN:

1461850

Hom.:

Cov.:

AF XY:

0.000518

AC XY:

377

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.00140

Gnomad4 AMR exome

AF:

0.000447

Gnomad4 ASJ exome

AF:

0.000115

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0000696

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000656

Gnomad4 OTH exome

AF:

0.000646

GnomAD4 genome

AF:

0.000512

AC:

AN:

152276

Hom.:

Cov.:

AF XY:

0.000470

AC XY:

AN XY:

74452

show subpopulations

Gnomad4 AFR

AF:

0.000914

Gnomad4 AMR

AF:

0.000457

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000470

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000357

Hom.:

Bravo

AF:

0.000582

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00182

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000305

AC:

EpiCase

AF:

0.000600

EpiControl

AF:

0.000415

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Dec 27, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 378 of the ALG2 protein (p.Arg378Cys). This variant is present in population databases (rs56393253, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with ALG2-related conditions. ClinVar contains an entry for this variant (Variation ID: 265036). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 12, 2022

The c.1132C>T (p.R378C) alteration is located in exon 2 (coding exon 2) of the ALG2 gene. This alteration results from a C to T substitution at nucleotide position 1132, causing the arginine (R) at amino acid position 378 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jun 30, 2022

Reported previously as a variant of uncertain significance identified with CDG molecular testing; however, no clinical information was provided (Jones et al., 2013); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23806237) -

ALG2-congenital disorder of glycosylation

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Jun 19, 2019

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.25

Cadd

Uncertain

Dann

Uncertain

1.0

DEOGEN2

Uncertain

0.60

D;.

Eigen

Pathogenic

0.72

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.71

T;T

M_CAP

Benign

0.057

MetaRNN

Benign

0.077

T;T

MetaSVM

Uncertain

0.10

MutationAssessor

Uncertain

2.4

M;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Benign

0.21

PROVEAN

Uncertain

-4.2

D;D

REVEL

Uncertain

0.37

Sift

Uncertain

0.016

D;D

Sift4G

Benign

0.099

T;D

Polyphen

0.99

D;D

Vest4

0.23

MVP

0.91

MPC

0.63

ClinPred

0.094

GERP RS

4.9

Varity_R

0.22

gMVP

0.51

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over