rs35055733

Positions:

• chr9-99221766-G-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_033087.4(ALG2):​c.129C>G​(p.Arg43=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0199 in 1,598,624 control chromosomes in the GnomAD database, including 446 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (60 hom., cov: 33)
  • Exomes 𝑓: 0.020 (386 hom.)
• Consequence: ALG2 NM_033087.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.163

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP6: Variant 9-99221766-G-C is Benign according to our data. Variant chr9-99221766-G-C is described in ClinVar as [Benign]. Clinvar id is 262208.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.163 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0178 (2711/152320) while in subpopulation NFE AF= 0.0238 (1620/68016). AF 95% confidence interval is 0.0229. There are 60 homozygotes in gnomad4. There are 1408 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 60 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALG2	NM_033087.4	c.129C>G	p.Arg43=	synonymous_variant	1/2	ENST00000476832.2	NP_149078.1
ALG2	NR_024532.2	n.177C>G		non_coding_transcript_exon_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALG2	ENST00000476832.2	c.129C>G	p.Arg43=	synonymous_variant	1/2	1	NM_033087.4	ENSP00000417764	P1
ALG2	ENST00000238477.5	c.129C>G	p.Arg43=	synonymous_variant, NMD_transcript_variant	1/3	2		ENSP00000432675

Frequencies

GnomAD3 genomes AF: 0.0178 AC: 2711 AN: 152202 Hom.: 60 Cov.: 33

Gnomad AFR AF: 0.00321

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00733

Gnomad ASJ AF: 0.00922

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0101

Gnomad FIN AF: 0.0687

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0238

Gnomad OTH AF: 0.0148

GnomAD3 exomes AF: 0.0176 AC: 3946 AN: 224496 Hom.: 75 AF XY: 0.0178 AC XY: 2215 AN XY: 124752

Gnomad AFR exome AF: 0.00263

Gnomad AMR exome AF: 0.00610

Gnomad ASJ exome AF: 0.00919

Gnomad EAS exome AF: 0.000114

Gnomad SAS exome AF: 0.0108

Gnomad FIN exome AF: 0.0685

Gnomad NFE exome AF: 0.0233

Gnomad OTH exome AF: 0.0170

GnomAD4 exome AF: 0.0201 AC: 29084 AN: 1446304 Hom.: 386 Cov.: 32 AF XY: 0.0199 AC XY: 14315 AN XY: 720032

Gnomad4 AFR exome AF: 0.00221

Gnomad4 AMR exome AF: 0.00703

Gnomad4 ASJ exome AF: 0.00844

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0104

Gnomad4 FIN exome AF: 0.0646

Gnomad4 NFE exome AF: 0.0217

Gnomad4 OTH exome AF: 0.0158

GnomAD4 genome AF: 0.0178 AC: 2711 AN: 152320 Hom.: 60 Cov.: 33 AF XY: 0.0189 AC XY: 1408 AN XY: 74496

Gnomad4 AFR AF: 0.00320

Gnomad4 AMR AF: 0.00732

Gnomad4 ASJ AF: 0.00922

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00995

Gnomad4 FIN AF: 0.0687

Gnomad4 NFE AF: 0.0238

Gnomad4 OTH AF: 0.0147

Alfa AF: 0.0197 Hom.: 26

Bravo AF: 0.0122

Asia WGS AF: 0.00462 AC: 16 AN: 3478

EpiCase AF: 0.0205

EpiControl AF: 0.0197

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 17, 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. -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 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
BayesDel_noAF	Benign	-0.37
CADD	Benign	10
DANN	Benign	0.84

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: rs35055733; hg19: chr9-101984048;