9-99217985-A-G

Variant names:

• chr9-99217985-A-G
• rs764916897
• NM_033087.4:c.1200T>C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 2P and 11B. PM2 BP4_Strong BP6_Moderate BP7 BS1

The NM_033087.4(ALG2):​c.1200T>C​(p.Pro400Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000186 in 1,614,112 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00020 (0 hom.)
• Consequence: ALG2 NM_033087.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -0.922

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 -9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 9-99217985-A-G is Benign according to our data. Variant chr9-99217985-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 533480.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.922 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.000201 (294/1461890) while in subpopulation NFE AF= 0.000263 (292/1112012). AF 95% confidence interval is 0.000238. There are 0 homozygotes in gnomad4_exome. There are 136 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALG2	NM_033087.4	c.1200T>C	p.Pro400Pro	synonymous_variant	Exon 2 of 2	ENST00000476832.2	NP_149078.1
ALG2	XM_047423996.1	c.921T>C	p.Pro307Pro	synonymous_variant	Exon 2 of 2		XP_047279952.1
ALG2	NR_024532.2	n.1407T>C		non_coding_transcript_exon_variant	Exon 3 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALG2	ENST00000476832.2	c.1200T>C	p.Pro400Pro	synonymous_variant	Exon 2 of 2	1	NM_033087.4	ENSP00000417764.1
ALG2	ENST00000319033.7	c.921T>C	p.Pro307Pro	synonymous_variant	Exon 2 of 2	1		ENSP00000326609.6
ALG2	ENST00000238477.5	n.*942T>C		non_coding_transcript_exon_variant	Exon 3 of 3	2		ENSP00000432675.2
ALG2	ENST00000238477.5	n.*942T>C		3_prime_UTR_variant	Exon 3 of 3	2		ENSP00000432675.2

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152222 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 251474 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135910

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000201 AC: 294 AN: 1461890 Hom.: 0 Cov.: 31 AF XY: 0.000187 AC XY: 136 AN XY: 727246

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000263

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152222 Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3 AN XY: 74370

Gnomad4 AFR AF: 0.0000965

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000772 Hom.: 0

Bravo AF: 0.0000718

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

ALG2-related disorder Benign:1

Aug 16, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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

Jan 22, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.96
DANN	Benign	0.62

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: rs764916897; hg19: chr9-101980267;