chr9-99221865-G-C

Position:

chr9-99221865-G-C

Variant summary

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

The NM_033087.4(ALG2):c.30C>G(p.Asp10Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00374 in 1,591,628 control chromosomes in the GnomAD database, including 115 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 (★★).

Frequency

Genomes: 𝑓 0.015 ( 34 hom., cov: 33)

Exomes 𝑓: 0.0026 ( 81 hom. )

Consequence

ALG2
NM_033087.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.972

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=0.0054671764).

BP6

Variant 9-99221865-G-C is Benign according to our data. Variant chr9-99221865-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 235651.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-99221865-G-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0146 (2229/152290) while in subpopulation AFR AF= 0.0486 (2018/41558). AF 95% confidence interval is 0.0468. There are 34 homozygotes in gnomad4. There are 1093 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 34 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALG2	NM_033087.4 linkuse as main transcript	c.30C>G	p.Asp10Glu	missense_variant	1/2	ENST00000476832.2	NP_149078.1
ALG2	NR_024532.2 linkuse as main transcript	n.78C>G		non_coding_transcript_exon_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALG2	ENST00000476832.2 linkuse as main transcript	c.30C>G	p.Asp10Glu	missense_variant	1/2	1	NM_033087.4	ENSP00000417764	P1	Q9H553-1
ALG2	ENST00000238477.5 linkuse as main transcript	c.30C>G	p.Asp10Glu	missense_variant, NMD_transcript_variant	1/3	2		ENSP00000432675

Frequencies

GnomAD3 genomes

AF:

0.0145

AC:

2200

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0480

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00510

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0197

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.0129

GnomAD3 exomes

AF:

0.00609

AC:

1334

AN:

219054

Hom.:

AF XY:

0.00582

AC XY:

708

AN XY:

121676

show subpopulations

Gnomad AFR exome

AF:

0.0514

Gnomad AMR exome

AF:

0.00213

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000579

Gnomad SAS exome

AF:

0.0185

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000120

Gnomad OTH exome

AF:

0.00343

GnomAD4 exome

AF:

0.00259

AC:

3728

AN:

1439338

Hom.:

Cov.:

AF XY:

0.00293

AC XY:

2093

AN XY:

715500

show subpopulations

Gnomad4 AFR exome

AF:

0.0492

Gnomad4 AMR exome

AF:

0.00270

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000760

Gnomad4 SAS exome

AF:

0.0180

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000911

Gnomad4 OTH exome

AF:

0.00492

GnomAD4 genome

AF:

0.0146

AC:

2229

AN:

152290

Hom.:

Cov.:

AF XY:

0.0147

AC XY:

1093

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.0486

Gnomad4 AMR

AF:

0.00510

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0193

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.0128

Alfa

AF:

0.000213

Hom.:

Bravo

AF:

0.0164

ESP6500AA

AF:

0.0465

AC:

202

ESP6500EA

AF:

0.000117

AC:

ExAC

AF:

0.00650

AC:

774

Asia WGS

AF:

0.0190

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 23, 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)	Feb 01, 2016	- -

not provided

Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 10, 2016	- -

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 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.62

CADD

Benign

0.14

DANN

Benign

0.65

DEOGEN2

Benign

0.063

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.058

LIST_S2

Benign

0.36

MetaRNN

Benign

0.0055

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.1

MutationTaster

Benign

1.0

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.050

REVEL

Benign

0.10

Sift

Benign

0.57

Sift4G

Benign

0.25

Polyphen

0.0

Vest4

0.13

MutPred

0.17

Gain of glycosylation at P13 (P = 0.1127);

MVP

0.52

MPC

0.17

ClinPred

0.00071

GERP RS

0.80

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.048

gMVP

0.28

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