rs61744789

Positions:

• chr9-99221811-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_033087.4(ALG2):​c.84C>G​(p.Gly28=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00244 in 1,597,644 control chromosomes in the GnomAD database, including 80 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0034 (11 hom., cov: 33)
  • Exomes 𝑓: 0.0023 (69 hom.)
• Consequence: ALG2 NM_033087.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.0440

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 9-99221811-G-C is Benign according to our data. Variant chr9-99221811-G-C is described in ClinVar as [Benign]. Clinvar id is 193473.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.044 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0538 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALG2	NM_033087.4	c.84C>G	p.Gly28=	synonymous_variant	1/2	ENST00000476832.2
ALG2	NR_024532.2	n.132C>G		non_coding_transcript_exon_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALG2	ENST00000476832.2	c.84C>G	p.Gly28=	synonymous_variant	1/2	1	NM_033087.4	P1
ALG2	ENST00000238477.5	c.84C>G	p.Gly28=	synonymous_variant, NMD_transcript_variant	1/3	2

Frequencies

GnomAD3 genomes AF: 0.00346 AC: 526 AN: 152242 Hom.: 11 Cov.: 33

Gnomad AFR AF: 0.000772

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0105

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0591

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00885 AC: 1987 AN: 224464 Hom.: 40 AF XY: 0.00709 AC XY: 882 AN XY: 124482

Gnomad AFR exome AF: 0.00107

Gnomad AMR exome AF: 0.0261

Gnomad ASJ exome AF: 0.000105

Gnomad EAS exome AF: 0.0576

Gnomad SAS exome AF: 0.00132

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000138

Gnomad OTH exome AF: 0.00387

GnomAD4 exome AF: 0.00233 AC: 3370 AN: 1445284 Hom.: 69 Cov.: 32 AF XY: 0.00211 AC XY: 1515 AN XY: 719426

Gnomad4 AFR exome AF: 0.000389

Gnomad4 AMR exome AF: 0.0244

Gnomad4 ASJ exome AF: 0.0000384

Gnomad4 EAS exome AF: 0.0451

Gnomad4 SAS exome AF: 0.00161

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000106

Gnomad4 OTH exome AF: 0.00366

GnomAD4 genome AF: 0.00344 AC: 524 AN: 152360 Hom.: 11 Cov.: 33 AF XY: 0.00376 AC XY: 280 AN XY: 74508

Gnomad4 AFR AF: 0.000769

Gnomad4 AMR AF: 0.0104

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0592

Gnomad4 SAS AF: 0.00186

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.00236

Alfa AF: 0.00126 Hom.: 0

Bravo AF: 0.00467

Asia WGS AF: 0.0260 AC: 91 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 14, 2016	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)	Apr 09, 2015	- -

ALG2-congenital disorder of glycosylation;C4015597:Congenital myasthenic syndrome 14 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 26, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	5.1
DANN	Benign	0.79

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

Other links and lift over

dbSNP: rs61744789; hg19: chr9-101984093;