NM_033087.4:c.17G>C

Variant names:

• chr9-99221878-C-G
• rs180849348
• NM_033087.4:c.17G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_033087.4(ALG2):​c.17G>C​(p.Gly6Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0102 in 1,588,892 control chromosomes in the GnomAD database, including 104 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G6R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0077 (6 hom., cov: 33)
  • Exomes 𝑓: 0.011 (98 hom.)
• Consequence: ALG2 NM_033087.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -1.53
• Publications: 6 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]

SEC61B (HGNC:16993): (SEC61 translocon subunit beta) The Sec61 complex is the central component of the protein translocation apparatus of the endoplasmic reticulum (ER) membrane. Oligomers of the Sec61 complex form a transmembrane channel where proteins are translocated across and integrated into the ER membrane. This complex consists of three membrane proteins- alpha, beta, and gamma. This gene encodes the beta-subunit protein. The Sec61 subunits are also observed in the post-ER compartment, suggesting that these proteins can escape the ER and recycle back. There is evidence for multiple polyadenylated sites for this transcript. [provided by RefSeq, Jul 2008]

SEC61B Gene-Disease associations (from GenCC):

• polycystic liver disease 1

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• SEC61B-related polycystic liver disease

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0025829375).
• BP6: Variant 9-99221878-C-G is Benign according to our data. Variant chr9-99221878-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 166675.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00767 (1168/152344) while in subpopulation NFE AF = 0.0103 (698/68026). AF 95% confidence interval is 0.00963. There are 6 homozygotes in GnomAd4. There are 604 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AR,Unknown 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALG2	NM_033087.4	MANE Select	c.17G>C	p.Gly6Ala	missense	Exon 1 of 2	NP_149078.1
	ALG2	NR_024532.2		n.65G>C		non_coding_transcript_exon	Exon 1 of 3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALG2	ENST00000476832.2	TSL:1 MANE Select	c.17G>C	p.Gly6Ala	missense	Exon 1 of 2	ENSP00000417764.1
	ALG2	ENST00000238477.5	TSL:2	n.17G>C		non_coding_transcript_exon	Exon 1 of 3	ENSP00000432675.2
	SEC61B	ENST00000498603.5	TSL:3	c.-453C>G		upstream_gene	N/A	ENSP00000474122.1

Frequencies

GnomAD3 genomes AF: 0.00767 AC: 1168 AN: 152226 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.00200

Gnomad AMI AF: 0.0274

Gnomad AMR AF: 0.00877

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.0187

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0103

Gnomad OTH AF: 0.00621

GnomAD2 exomes AF: 0.00684 AC: 1463 AN: 213748 AF XY: 0.00689

Gnomad AFR exome AF: 0.00253

Gnomad AMR exome AF: 0.00579

Gnomad ASJ exome AF: 0.000108

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0154

Gnomad NFE exome AF: 0.00959

Gnomad OTH exome AF: 0.00985

GnomAD4 exome AF: 0.0105 AC: 15096 AN: 1436548 Hom.: 98 Cov.: 32 AF XY: 0.0103 AC XY: 7368 AN XY: 713816

African (AFR) AF: 0.00153 AC: 51 AN: 33260

American (AMR) AF: 0.00600 AC: 265 AN: 44140

Ashkenazi Jewish (ASJ) AF: 0.000116 AC: 3 AN: 25836

East Asian (EAS) AF: 0.00 AC: 0 AN: 39398

South Asian (SAS) AF: 0.00406 AC: 346 AN: 85198

European-Finnish (FIN) AF: 0.0143 AC: 529 AN: 37112

Middle Eastern (MID) AF: 0.00202 AC: 10 AN: 4954

European-Non Finnish (NFE) AF: 0.0121 AC: 13340 AN: 1107046

Other (OTH) AF: 0.00926 AC: 552 AN: 59604

GnomAD4 genome AF: 0.00767 AC: 1168 AN: 152344 Hom.: 6 Cov.: 33 AF XY: 0.00811 AC XY: 604 AN XY: 74500

African (AFR) AF: 0.00200 AC: 83 AN: 41584

American (AMR) AF: 0.00875 AC: 134 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.00290 AC: 14 AN: 4828

European-Finnish (FIN) AF: 0.0187 AC: 199 AN: 10626

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

European-Non Finnish (NFE) AF: 0.0103 AC: 698 AN: 68026

Other (OTH) AF: 0.00615 AC: 13 AN: 2114

Alfa AF: 0.00402 Hom.: 2

Bravo AF: 0.00672

TwinsUK AF: 0.0135 AC: 50

ALSPAC AF: 0.0106 AC: 41

ESP6500AA AF: 0.00209 AC: 9

ESP6500EA AF: 0.00742 AC: 63

ExAC AF: 0.00623 AC: 739

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Aug 29, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ALG2: BP4, BS1, BS2

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

not specified Benign:2

Mar 10, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 22, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 02, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ALG2-related disorder Benign:1

Dec 03, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	0.013
DANN	Benign	0.46
DEOGEN2	Benign	0.064	T
Eigen	Benign	-2.5
Eigen_PC	Benign	-2.6
FATHMM_MKL	Benign	0.033	N
LIST_S2	Benign	0.41	T
MetaRNN	Benign	0.0026	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	0.90	L
PhyloP100		-1.5
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.020	N
REVEL	Benign	0.15
Sift	Benign	0.54	T
Sift4G	Benign	0.40	T
Polyphen		0.0	B
Vest4		0.17
MVP		0.41
MPC		0.20
ClinPred		0.013	T
GERP RS		-9.3
PromoterAI		0.084	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.025
gMVP		0.54
Mutation Taster		=97/3	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: rs180849348; hg19: chr9-101984160; COSMIC: COSV53059013; COSMIC: COSV53059013;