rs35626507

Variant names:

• chr9-99218085-A-G
• rs35626507
• NM_033087.4:c.1100T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. V367V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.055 (310 hom., cov: 32)
  • Exomes 𝑓: 0.074 (4404 hom.)
• Consequence: ALG2 NM_033087.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.951
• Publications: 20 publications found

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 Gene-Disease associations (from GenCC):

• congenital myasthenic syndrome 14

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• ALG2-congenital disorder of glycosylation

  Inheritance: Unknown, AR Classification: STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen, G2P, Orphanet
• congenital myasthenic syndromes with glycosylation defect

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033087.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALG2	NM_033087.4	MANE Select	c.1100T>C	p.Val367Ala	missense	Exon 2 of 2	NP_149078.1	Q9H553-1
	ALG2	NR_024532.2		n.1307T>C		non_coding_transcript_exon	Exon 3 of 3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALG2	ENST00000476832.2	TSL:1 MANE Select	c.1100T>C	p.Val367Ala	missense	Exon 2 of 2	ENSP00000417764.1	Q9H553-1
	ALG2	ENST00000319033.7	TSL:1	c.821T>C	p.Val274Ala	missense	Exon 2 of 2	ENSP00000326609.6	Q9H553-2
	ALG2	ENST00000906837.1		c.953T>C	p.Val318Ala	missense	Exon 2 of 2	ENSP00000576896.1

Frequencies

GnomAD3 genomes AF: 0.0548 AC: 8345 AN: 152162 Hom.: 310 Cov.: 32

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

GnomAD2 exomes AF: 0.0615 AC: 15453 AN: 251290 AF XY: 0.0635

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 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.: 31 AF XY: 0.0739 AC XY: 53703 AN XY: 727128

African (AFR) AF: 0.0116 AC: 388 AN: 33426

American (AMR) AF: 0.0609 AC: 2722 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.0485 AC: 1267 AN: 26126

East Asian (EAS) AF: 0.00960 AC: 381 AN: 39698

South Asian (SAS) AF: 0.0652 AC: 5626 AN: 86246

European-Finnish (FIN) AF: 0.0579 AC: 3093 AN: 53418

Middle Eastern (MID) AF: 0.0827 AC: 477 AN: 5766

European-Non Finnish (NFE) AF: 0.0811 AC: 90195 AN: 1111876

Other (OTH) AF: 0.0686 AC: 4144 AN: 60384

GnomAD4 genome AF: 0.0548 AC: 8342 AN: 152280 Hom.: 310 Cov.: 32 AF XY: 0.0536 AC XY: 3992 AN XY: 74452

African (AFR) AF: 0.0155 AC: 645 AN: 41562

American (AMR) AF: 0.0609 AC: 932 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0521 AC: 181 AN: 3472

East Asian (EAS) AF: 0.00928 AC: 48 AN: 5174

South Asian (SAS) AF: 0.0593 AC: 286 AN: 4826

European-Finnish (FIN) AF: 0.0549 AC: 582 AN: 10608

Middle Eastern (MID) AF: 0.0476 AC: 14 AN: 294

European-Non Finnish (NFE) AF: 0.0788 AC: 5361 AN: 68022

Other (OTH) AF: 0.0583 AC: 123 AN: 2110

Alfa AF: 0.0680 Hom.: 832

Bravo AF: 0.0536

TwinsUK AF: 0.0860 AC: 319

ALSPAC AF: 0.0848 AC: 327

ESP6500AA AF: 0.0188 AC: 83

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	1	ALG2-congenital disorder of glycosylation;C4015597:Congenital myasthenic syndrome 14 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.56	T
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	N
LIST_S2	Benign	0.79	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.67	N
PhyloP100		0.95
PrimateAI	Benign	0.29	T
PROVEAN	Benign	1.1	N
REVEL	Benign	0.083
Sift	Benign	0.38	T
Sift4G	Benign	0.53	T
Polyphen		0.0	B
Vest4		0.025
MPC		0.22
ClinPred		0.0027	T
GERP RS		0.73
Varity_R		0.028
gMVP		0.41
Mutation Taster		=97/3	polymorphism (auto)

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

Other links and lift over

dbSNP: rs35626507; hg19: chr9-101980367; COSMIC: COSV53059063; COSMIC: COSV53059063;