NM_033087.4:c.1226G>T

Variant names:

• chr9-99217959-C-A
• NM_033087.4:c.1226G>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_033087.4(ALG2):​c.1226G>T​(p.Arg409Leu) 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 1,461,878 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ALG2 NM_033087.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.50

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 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=0.21352404).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALG2	NM_033087.4	c.1226G>T	p.Arg409Leu	missense_variant	Exon 2 of 2	ENST00000476832.2	NP_149078.1
ALG2	XM_047423996.1	c.947G>T	p.Arg316Leu	missense_variant	Exon 2 of 2		XP_047279952.1
ALG2	NR_024532.2	n.1433G>T		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.1226G>T	p.Arg409Leu	missense_variant	Exon 2 of 2	1	NM_033087.4	ENSP00000417764.1
ALG2	ENST00000319033.7	c.947G>T	p.Arg316Leu	missense_variant	Exon 2 of 2	1		ENSP00000326609.6
ALG2	ENST00000238477.5	n.*968G>T		non_coding_transcript_exon_variant	Exon 3 of 3	2		ENSP00000432675.2
ALG2	ENST00000238477.5	n.*968G>T		3_prime_UTR_variant	Exon 3 of 3	2		ENSP00000432675.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461878 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727242

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.058	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	15
DANN	Benign	0.97
DEOGEN2	Benign	0.41	T;.
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.76	T;T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.21	T;T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	1.9	L;.
PrimateAI	Benign	0.24	T
PROVEAN	Uncertain	-2.7	D;D
REVEL	Benign	0.18
Sift	Benign	0.17	T;T
Sift4G	Benign	0.27	T;T
Polyphen		0.025	B;B
Vest4		0.23
MutPred		0.51		Loss of MoRF binding (P = 5e-04);.;
MVP		0.79
MPC		0.24
ClinPred		0.31	T
GERP RS		2.3
Varity_R		0.084
gMVP		0.47

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.

Other links and lift over

hg19: chr9-101980241;