rs7023652

Positions:

• chr9-99221865-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.972

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 -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	c.30C>G	p.Asp10Glu	missense_variant	1/2	ENST00000476832.2	NP_149078.1
ALG2	NR_024532.2	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	c.30C>G	p.Asp10Glu	missense_variant	1/2	1	NM_033087.4	ENSP00000417764	P1
ALG2	ENST00000238477.5	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.: 30 Cov.: 33

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.: 30 AF XY: 0.00582 AC XY: 708 AN XY: 121676

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.: 81 Cov.: 32 AF XY: 0.00293 AC XY: 2093 AN XY: 715500

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.: 34 Cov.: 33 AF XY: 0.0147 AC XY: 1093 AN XY: 74474

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.: 0

Bravo AF: 0.0164

ESP6500AA AF: 0.0465 AC: 202

ESP6500EA AF: 0.000117 AC: 1

ExAC AF: 0.00650 AC: 774

Asia WGS AF: 0.0190 AC: 68 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

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	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	0.14
DANN	Benign	0.65
DEOGEN2	Benign	0.063	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.058	N
LIST_S2	Benign	0.36	T
MetaRNN	Benign	0.0055	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.050	N
REVEL	Benign	0.10
Sift	Benign	0.57	T
Sift4G	Benign	0.25	T
Polyphen		0.0	B
Vest4		0.13
MutPred		0.17		Gain of glycosylation at P13 (P = 0.1127);
MVP		0.52
MPC		0.17
ClinPred		0.00071	T
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

Other links and lift over

dbSNP: rs7023652; hg19: chr9-101984147;