dbSNP rs749613639: ALG2:p.Val416Leu (chr9-99217939-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_033087.4(ALG2):c.1246G>T(p.Val416Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,820 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Synonymous variant affecting the same amino acid position (i.e. V416V) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

ALG2
NM_033087.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.126

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.09556106).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALG2	NM_033087.4 link	c.1246G>T	p.Val416Leu	missense_variant	Exon 2 of 2	ENST00000476832.2	NP_149078.1	Q9H553-1A0A024R184
ALG2	XM_047423996.1 link	c.967G>T	p.Val323Leu	missense_variant	Exon 2 of 2		XP_047279952.1
ALG2	NR_024532.2 link	n.1453G>T		non_coding_transcript_exon_variant	Exon 3 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ALG2	ENST00000476832.2 link	c.1246G>T	p.Val416Leu	missense_variant	Exon 2 of 2	1	NM_033087.4	ENSP00000417764.1	Q9H553-1
ALG2	ENST00000319033.7 link	c.967G>T	p.Val323Leu	missense_variant	Exon 2 of 2	1		ENSP00000326609.6	Q9H553-2
ALG2	ENST00000238477.5 link	n.*988G>T		non_coding_transcript_exon_variant	Exon 3 of 3	2		ENSP00000432675.2	A0A0A0MTE0
ALG2	ENST00000238477.5 link	n.*988G>T		3_prime_UTR_variant	Exon 3 of 3	2		ENSP00000432675.2	A0A0A0MTE0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461820

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727206

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.029

BayesDel_noAF

Benign

-0.28

CADD

Benign

7.9

DANN

Benign

0.93

DEOGEN2

Benign

0.087

T;.

Eigen

Benign

-0.88

Eigen_PC

Benign

-0.85

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.79

T;T

M_CAP

Benign

0.048

MetaRNN

Benign

0.096

T;T

MetaSVM

Benign

-0.81

MutationAssessor

Benign

0.0

N;.

PrimateAI

Benign

0.35

PROVEAN

Benign

-0.75

N;N

REVEL

Benign

0.17

Sift

Pathogenic

0.0

D;D

Sift4G

Benign

0.065

T;T

Polyphen

0.0010

B;B

Vest4

0.18

MutPred

0.44

Loss of methylation at K413 (P = 0.0536);.;

MVP

0.62

MPC

0.19

ClinPred

0.15

GERP RS

3.4

Varity_R

0.13

gMVP

0.37

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over