rs146770430

Positions:

chr9-99218710-T-C

Variant summary

Our verdict is Benign. Variant got -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. 15/21 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

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:

ALG2 (HGNC:):

ALG2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 390397.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=1}. Variant chr9-99218710-T-C is described in Lovd as [Likely_benign].

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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALG2	NM_033087.4 linkuse as main transcript	c.475A>G	p.Ile159Val	missense_variant	2/2	ENST00000476832.2	NP_149078.1	Q9H553-1A0A024R184
ALG2	XM_047423996.1 linkuse as main transcript	c.196A>G	p.Ile66Val	missense_variant	2/2		XP_047279952.1
ALG2	NR_024532.2 linkuse as main transcript	n.682A>G		non_coding_transcript_exon_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
ALG2	ENST00000476832.2 linkuse as main transcript	c.475A>G	p.Ile159Val	missense_variant	2/2	1	NM_033087.4	ENSP00000417764.1	Q9H553-1
ALG2	ENST00000319033.7 linkuse as main transcript	c.196A>G	p.Ile66Val	missense_variant	2/2	1		ENSP00000326609.6	Q9H553-2
ALG2	ENST00000238477.5 linkuse as main transcript	n.*217A>G		non_coding_transcript_exon_variant	3/3	2		ENSP00000432675.2	A0A0A0MTE0
ALG2	ENST00000238477.5 linkuse as main transcript	n.*217A>G		3_prime_UTR_variant	3/3	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

GnomAD3 exomes

AF:

0.000720

AC:

181

AN:

251480

Hom.:

AF XY:

0.000773

AC XY:

105

AN XY:

135918

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 SAS exome

AF:

0.000359

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

Gnomad4 AFR exome

AF:

0.000657

Gnomad4 AMR exome

AF:

0.000291

Gnomad4 ASJ exome

AF:

0.00681

Gnomad4 EAS exome

AF:

0.00416

Gnomad4 SAS exome

AF:

0.000452

Gnomad4 FIN exome

AF:

0.0000936

Gnomad4 NFE exome

AF:

0.000613

Gnomad4 OTH exome

AF:

0.00139

GnomAD4 genome

AF:

0.000604

AC:

AN:

152286

Hom.:

Cov.:

AF XY:

0.000618

AC XY:

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.000409

Gnomad4 AMR

AF:

0.000523

Gnomad4 ASJ

AF:

0.00749

Gnomad4 EAS

AF:

0.000771

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.000426

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00145

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

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	ALG2: BP4 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 02, 2018	- -

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

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -

ALG2-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 23, 2020

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

Likely benign, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Apr 08, 2020

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

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;.

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

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