9-99218085-A-G

Position:

chr9-99218085-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_033087.4(ALG2):c.1100T>C(p.Val367Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0723 in 1,613,910 control chromosomes in the GnomAD database, including 4,714 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 Benign (★★).

Frequency

Genomes: 𝑓 0.055 ( 310 hom., cov: 32)

Exomes 𝑓: 0.074 ( 4404 hom. )

Consequence

ALG2
NM_033087.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.951

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=0.0016386211).

BP6

Variant 9-99218085-A-G is Benign according to our data. Variant chr9-99218085-A-G is described in ClinVar as [Benign]. Clinvar id is 96236.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0771 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
ALG2	NM_033087.4 linkuse as main transcript	c.1100T>C	p.Val367Ala	missense_variant	2/2	ENST00000476832.2	NP_149078.1
ALG2	XM_047423996.1 linkuse as main transcript	c.821T>C	p.Val274Ala	missense_variant	2/2		XP_047279952.1
ALG2	NR_024532.2 linkuse as main transcript	n.1307T>C		non_coding_transcript_exon_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALG2	ENST00000476832.2 linkuse as main transcript	c.1100T>C	p.Val367Ala	missense_variant	2/2	1	NM_033087.4	ENSP00000417764	P1	Q9H553-1
ALG2	ENST00000319033.7 linkuse as main transcript	c.821T>C	p.Val274Ala	missense_variant	2/2	1		ENSP00000326609		Q9H553-2
ALG2	ENST00000238477.5 linkuse as main transcript	c.*842T>C		3_prime_UTR_variant, NMD_transcript_variant	3/3	2		ENSP00000432675

Frequencies

GnomAD3 genomes

AF:

0.0548

AC:

8345

AN:

152162

Hom.:

310

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0156

Gnomad AMI

AF:

0.186

Gnomad AMR

AF:

0.0611

Gnomad ASJ

AF:

0.0521

Gnomad EAS

AF:

0.00926

Gnomad SAS

AF:

0.0594

Gnomad FIN

AF:

0.0549

Gnomad MID

AF:

0.0443

Gnomad NFE

AF:

0.0788

Gnomad OTH

AF:

0.0589

GnomAD3 exomes

AF:

0.0615

AC:

15453

AN:

251290

Hom.:

578

AF XY:

0.0635

AC XY:

8621

AN XY:

135816

show subpopulations

Gnomad AFR exome

AF:

0.0139

Gnomad AMR exome

AF:

0.0610

Gnomad ASJ exome

AF:

0.0468

Gnomad EAS exome

AF:

0.00658

Gnomad SAS exome

AF:

0.0664

Gnomad FIN exome

AF:

0.0585

Gnomad NFE exome

AF:

0.0776

Gnomad OTH exome

AF:

0.0670

GnomAD4 exome

AF:

0.0741

AC:

108293

AN:

1461630

Hom.:

4404

Cov.:

AF XY:

0.0739

AC XY:

53703

AN XY:

727128

show subpopulations

Gnomad4 AFR exome

AF:

0.0116

Gnomad4 AMR exome

AF:

0.0609

Gnomad4 ASJ exome

AF:

0.0485

Gnomad4 EAS exome

AF:

0.00960

Gnomad4 SAS exome

AF:

0.0652

Gnomad4 FIN exome

AF:

0.0579

Gnomad4 NFE exome

AF:

0.0811

Gnomad4 OTH exome

AF:

0.0686

GnomAD4 genome

AF:

0.0548

AC:

8342

AN:

152280

Hom.:

310

Cov.:

AF XY:

0.0536

AC XY:

3992

AN XY:

74452

show subpopulations

Gnomad4 AFR

AF:

0.0155

Gnomad4 AMR

AF:

0.0609

Gnomad4 ASJ

AF:

0.0521

Gnomad4 EAS

AF:

0.00928

Gnomad4 SAS

AF:

0.0593

Gnomad4 FIN

AF:

0.0549

Gnomad4 NFE

AF:

0.0788

Gnomad4 OTH

AF:

0.0583

Alfa

AF:

0.0716

Hom.:

635

Bravo

AF:

0.0536

TwinsUK

AF:

0.0860

AC:

319

ALSPAC

AF:

0.0848

AC:

327

ESP6500AA

AF:

0.0188

AC:

ESP6500EA

AF:

0.0790

AC:

679

ExAC

AF:

0.0596

AC:

7238

Asia WGS

AF:

0.0400

AC:

139

AN:

3478

EpiCase

AF:

0.0795

EpiControl

AF:

0.0842

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 21, 2015	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)	Oct 04, 2012	- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.51

CADD

Benign

9.0

DANN

Benign

0.94

DEOGEN2

Benign

0.15

T;.

Eigen

Benign

-0.92

Eigen_PC

Benign

-0.83

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.79

T;T

MetaRNN

Benign

0.0016

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.67

N;.

MutationTaster

Benign

1.0

P;P

PrimateAI

Benign

0.29

PROVEAN

Benign

1.1

N;N

REVEL

Benign

0.083

Sift

Benign

0.38

T;T

Sift4G

Benign

0.53

T;T

Polyphen

0.0

B;B

Vest4

0.025

MPC

0.22

ClinPred

0.0027

GERP RS

0.73

Varity_R

0.028

gMVP

0.41

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