9-99221864-A-G

Position:

• chr9-99221864-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_033087.4(ALG2):​c.31T>C​(p.Ser11Pro) 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 1,591,414 control chromosomes in the GnomAD database, including 4,653 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.055 (312 hom., cov: 32)
  • Exomes 𝑓: 0.074 (4341 hom.)
• Consequence: ALG2 NM_033087.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.995

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0018701553).
• BP6: Variant 9-99221864-A-G is Benign according to our data. Variant chr9-99221864-A-G is described in ClinVar as [Benign]. Clinvar id is 96237.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0769 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALG2	NM_033087.4	c.31T>C	p.Ser11Pro	missense_variant	1/2	ENST00000476832.2	NP_149078.1
ALG2	NR_024532.2	n.79T>C		non_coding_transcript_exon_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALG2	ENST00000476832.2	c.31T>C	p.Ser11Pro	missense_variant	1/2	1	NM_033087.4	ENSP00000417764	P1
ALG2	ENST00000238477.5	c.31T>C	p.Ser11Pro	missense_variant, NMD_transcript_variant	1/3	2		ENSP00000432675

Frequencies

GnomAD3 genomes AF: 0.0549 AC: 8348 AN: 152164 Hom.: 312 Cov.: 32

Gnomad AFR AF: 0.0159

Gnomad AMI AF: 0.186

Gnomad AMR AF: 0.0613

Gnomad ASJ AF: 0.0522

Gnomad EAS AF: 0.00907

Gnomad SAS AF: 0.0598

Gnomad FIN AF: 0.0548

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0787

Gnomad OTH AF: 0.0578

GnomAD3 exomes AF: 0.0612 AC: 13394 AN: 218840 Hom.: 494 AF XY: 0.0631 AC XY: 7666 AN XY: 121530

Gnomad AFR exome AF: 0.0134

Gnomad AMR exome AF: 0.0609

Gnomad ASJ exome AF: 0.0470

Gnomad EAS exome AF: 0.00625

Gnomad SAS exome AF: 0.0666

Gnomad FIN exome AF: 0.0567

Gnomad NFE exome AF: 0.0772

Gnomad OTH exome AF: 0.0652

GnomAD4 exome AF: 0.0742 AC: 106746 AN: 1439132 Hom.: 4341 Cov.: 32 AF XY: 0.0740 AC XY: 52911 AN XY: 715350

Gnomad4 AFR exome AF: 0.0123

Gnomad4 AMR exome AF: 0.0606

Gnomad4 ASJ exome AF: 0.0484

Gnomad4 EAS exome AF: 0.00911

Gnomad4 SAS exome AF: 0.0652

Gnomad4 FIN exome AF: 0.0561

Gnomad4 NFE exome AF: 0.0811

Gnomad4 OTH exome AF: 0.0686

GnomAD4 genome AF: 0.0548 AC: 8345 AN: 152282 Hom.: 312 Cov.: 32 AF XY: 0.0536 AC XY: 3990 AN XY: 74464

Gnomad4 AFR AF: 0.0158

Gnomad4 AMR AF: 0.0611

Gnomad4 ASJ AF: 0.0522

Gnomad4 EAS AF: 0.00909

Gnomad4 SAS AF: 0.0596

Gnomad4 FIN AF: 0.0548

Gnomad4 NFE AF: 0.0787

Gnomad4 OTH AF: 0.0572

Alfa AF: 0.0740 Hom.: 554

Bravo AF: 0.0538

TwinsUK AF: 0.0868 AC: 322

ALSPAC AF: 0.0854 AC: 329

ESP6500AA AF: 0.0161 AC: 70

ESP6500EA AF: 0.0698 AC: 596

ExAC AF: 0.0568 AC: 6757

Asia WGS AF: 0.0400 AC: 138 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 04, 2012	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 21, 2015	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:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	0.51
DANN	Benign	0.42
DEOGEN2	Benign	0.068	T
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.015	N
LIST_S2	Benign	0.20	T
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.20	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.31	N
REVEL	Benign	0.18
Sift	Benign	0.39	T
Sift4G	Benign	0.29	T
Polyphen		0.0	B
Vest4		0.11
MPC		0.23
ClinPred		0.0088	T
GERP RS		-9.3
Varity_R		0.081
gMVP		0.35

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: rs11545137; hg19: chr9-101984146;