9-99218425-A-G

Variant names:

• chr9-99218425-A-G
• rs62562374
• NM_033087.4:c.760T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_033087.4(ALG2):​c.760T>C​(p.Leu254Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00491 in 1,614,186 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0040 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0050 (28 hom.)
• Consequence: ALG2 NM_033087.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.16
• Publications: 2 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 9-99218425-A-G is Benign according to our data. Variant chr9-99218425-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 96238.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.16 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00396 (603/152292) while in subpopulation NFE AF = 0.00697 (474/68022). AF 95% confidence interval is 0.00645. There are 2 homozygotes in GnomAd4. There are 281 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 Unknown,AR gene

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.760T>C	p.Leu254Leu	synonymous	Exon 2 of 2	NP_149078.1	Q9H553-1
	ALG2	NR_024532.2		n.967T>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.760T>C	p.Leu254Leu	synonymous	Exon 2 of 2	ENSP00000417764.1	Q9H553-1
	ALG2	ENST00000319033.7	TSL:1	c.481T>C	p.Leu161Leu	synonymous	Exon 2 of 2	ENSP00000326609.6	Q9H553-2
	ALG2	ENST00000906837.1		c.613T>C	p.Leu205Leu	synonymous	Exon 2 of 2	ENSP00000576896.1

Frequencies

GnomAD3 genomes AF: 0.00396 AC: 603 AN: 152174 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000603

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.00340

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00395

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00697

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00396 AC: 995 AN: 251486 AF XY: 0.00402

Gnomad AFR exome AF: 0.000677

Gnomad AMR exome AF: 0.00176

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00333

Gnomad NFE exome AF: 0.00705

Gnomad OTH exome AF: 0.00407

GnomAD4 exome AF: 0.00501 AC: 7326 AN: 1461894 Hom.: 28 Cov.: 31 AF XY: 0.00497 AC XY: 3615 AN XY: 727248

African (AFR) AF: 0.000657 AC: 22 AN: 33480

American (AMR) AF: 0.00161 AC: 72 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000268 AC: 7 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000962 AC: 83 AN: 86258

European-Finnish (FIN) AF: 0.00451 AC: 241 AN: 53420

Middle Eastern (MID) AF: 0.000693 AC: 4 AN: 5768

European-Non Finnish (NFE) AF: 0.00600 AC: 6670 AN: 1112012

Other (OTH) AF: 0.00376 AC: 227 AN: 60396

GnomAD4 genome AF: 0.00396 AC: 603 AN: 152292 Hom.: 2 Cov.: 33 AF XY: 0.00377 AC XY: 281 AN XY: 74476

African (AFR) AF: 0.000602 AC: 25 AN: 41556

American (AMR) AF: 0.00340 AC: 52 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.000830 AC: 4 AN: 4820

European-Finnish (FIN) AF: 0.00395 AC: 42 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00697 AC: 474 AN: 68022

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.00348 Hom.: 2

Bravo AF: 0.00341

EpiCase AF: 0.00692

EpiControl AF: 0.00522

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	ALG2-congenital disorder of glycosylation;C4015597:Congenital myasthenic syndrome 14 (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	2.5
DANN	Benign	0.57
PhyloP100		1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

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: rs62562374; hg19: chr9-101980707;