9-99221878-C-G

Position:

chr9-99221878-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_033087.4(ALG2):c.17G>C(p.Gly6Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0102 in 1,588,892 control chromosomes in the GnomAD database, including 104 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G6R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0077 ( 6 hom., cov: 33)

Exomes 𝑓: 0.011 ( 98 hom. )

Consequence

ALG2
NM_033087.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -1.53

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0025829375).

BP6

Variant 9-99221878-C-G is Benign according to our data. Variant chr9-99221878-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 166675.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00767 (1168/152344) while in subpopulation NFE AF= 0.0103 (698/68026). AF 95% confidence interval is 0.00963. There are 6 homozygotes in gnomad4. There are 604 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALG2	NM_033087.4 linkuse as main transcript	c.17G>C	p.Gly6Ala	missense_variant	1/2	ENST00000476832.2
ALG2	NR_024532.2 linkuse as main transcript	n.65G>C		non_coding_transcript_exon_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALG2	ENST00000476832.2 linkuse as main transcript	c.17G>C	p.Gly6Ala	missense_variant	1/2	1	NM_033087.4	P1	Q9H553-1
ALG2	ENST00000238477.5 linkuse as main transcript	c.17G>C	p.Gly6Ala	missense_variant, NMD_transcript_variant	1/3	2

Frequencies

GnomAD3 genomes

AF:

0.00767

AC:

1168

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00200

Gnomad AMI

AF:

0.0274

Gnomad AMR

AF:

0.00877

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00290

Gnomad FIN

AF:

0.0187

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0103

Gnomad OTH

AF:

0.00621

GnomAD3 exomes

AF:

0.00684

AC:

1463

AN:

213748

Hom.:

AF XY:

0.00689

AC XY:

819

AN XY:

118856

show subpopulations

Gnomad AFR exome

AF:

0.00253

Gnomad AMR exome

AF:

0.00579

Gnomad ASJ exome

AF:

0.000108

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00344

Gnomad FIN exome

AF:

0.0154

Gnomad NFE exome

AF:

0.00959

Gnomad OTH exome

AF:

0.00985

GnomAD4 exome

AF:

0.0105

AC:

15096

AN:

1436548

Hom.:

Cov.:

AF XY:

0.0103

AC XY:

7368

AN XY:

713816

show subpopulations

Gnomad4 AFR exome

AF:

0.00153

Gnomad4 AMR exome

AF:

0.00600

Gnomad4 ASJ exome

AF:

0.000116

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00406

Gnomad4 FIN exome

AF:

0.0143

Gnomad4 NFE exome

AF:

0.0121

Gnomad4 OTH exome

AF:

0.00926

GnomAD4 genome

AF:

0.00767

AC:

1168

AN:

152344

Hom.:

Cov.:

AF XY:

0.00811

AC XY:

604

AN XY:

74500

show subpopulations

Gnomad4 AFR

AF:

0.00200

Gnomad4 AMR

AF:

0.00875

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00290

Gnomad4 FIN

AF:

0.0187

Gnomad4 NFE

AF:

0.0103

Gnomad4 OTH

AF:

0.00615

Alfa

AF:

0.00402

Hom.:

Bravo

AF:

0.00672

TwinsUK

AF:

0.0135

AC:

ALSPAC

AF:

0.0106

AC:

ESP6500AA

AF:

0.00209

AC:

ESP6500EA

AF:

0.00742

AC:

ExAC

AF:

0.00623

AC:

739

Asia WGS

AF:

0.00231

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Aug 29, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	ALG2: BP4, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 22, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 10, 2014	- -

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

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 02, 2021	- -

ALG2-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 03, 2019

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

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.49

CADD

Benign

0.013

DANN

Benign

0.46

DEOGEN2

Benign

0.064

Eigen

Benign

-2.5

Eigen_PC

Benign

-2.6

FATHMM_MKL

Benign

0.033

LIST_S2

Benign

0.41

MetaRNN

Benign

0.0026

MetaSVM

Benign

-0.86

MutationAssessor

Benign

0.90

MutationTaster

Benign

1.0

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.020

REVEL

Benign

0.15

Sift

Benign

0.54

Sift4G

Benign

0.40

Polyphen

0.0

Vest4

0.17

MVP

0.41

MPC

0.20

ClinPred

0.013

GERP RS

-9.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.025

gMVP

0.54

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