9-99218425-A-G

Position:

• chr9-99218425-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_033087.4(ALG2):​c.760T>C​(p.Leu254=) 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

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=-0.81).
• BP6: Variant 9-99218425-A-G is Benign according to our data. Variant chr9-99218425-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 96238.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-99218425-A-G is described in Lovd as [Likely_benign].
• 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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALG2	NM_033087.4	c.760T>C	p.Leu254=	synonymous_variant	2/2	ENST00000476832.2	NP_149078.1
ALG2	XM_047423996.1	c.481T>C	p.Leu161=	synonymous_variant	2/2		XP_047279952.1
ALG2	NR_024532.2	n.967T>C		non_coding_transcript_exon_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALG2	ENST00000476832.2	c.760T>C	p.Leu254=	synonymous_variant	2/2	1	NM_033087.4	ENSP00000417764	P1
ALG2	ENST00000319033.7	c.481T>C	p.Leu161=	synonymous_variant	2/2	1		ENSP00000326609
ALG2	ENST00000238477.5	c.*502T>C		3_prime_UTR_variant, NMD_transcript_variant	3/3	2		ENSP00000432675

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

GnomAD3 exomes AF: 0.00396 AC: 995 AN: 251486 Hom.: 4 AF XY: 0.00402 AC XY: 546 AN XY: 135916

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 SAS exome AF: 0.000784

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

Gnomad4 AFR exome AF: 0.000657

Gnomad4 AMR exome AF: 0.00161

Gnomad4 ASJ exome AF: 0.000268

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000962

Gnomad4 FIN exome AF: 0.00451

Gnomad4 NFE exome AF: 0.00600

Gnomad4 OTH exome AF: 0.00376

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

Gnomad4 AFR AF: 0.000602

Gnomad4 AMR AF: 0.00340

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000830

Gnomad4 FIN AF: 0.00395

Gnomad4 NFE AF: 0.00697

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00401 Hom.: 2

Bravo AF: 0.00341

EpiCase AF: 0.00692

EpiControl AF: 0.00522

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	ALG2: BP4, BP7, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 12, 2021	- -

ALG2-congenital disorder of glycosylation;C4015597:Congenital myasthenic syndrome 14 Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Nov 03, 2021	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jan 12, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	2.5
DANN	Benign	0.57
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs62562374; hg19: chr9-101980707;