22-49909914-G-T

Variant names:

• chr22-49909914-G-T
• rs777173365
• NM_024105.4:c.644C>A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_024105.4(ALG12):​c.644C>A​(p.Pro215Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,756 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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: ALG12 NM_024105.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.09

Genes affected

ALG12 (HGNC:19358): (ALG12 alpha-1,6-mannosyltransferase) This gene encodes a member of the glycosyltransferase 22 family. The encoded protein catalyzes the addition of the eighth mannose residue in an alpha-1,6 linkage onto the dolichol-PP-oligosaccharide precursor (dolichol-PP-Man(7)GlcNAc(2)) required for protein glycosylation. Mutations in this gene have been associated with congenital disorder of glycosylation type Ig (CDG-Ig)characterized by abnormal N-glycosylation. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.91

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALG12	NM_024105.4	c.644C>A	p.Pro215Gln	missense_variant	Exon 5 of 10	ENST00000330817.11	NP_077010.1
ALG12	XM_017028936.2	c.644C>A	p.Pro215Gln	missense_variant	Exon 5 of 10		XP_016884425.1
ALG12	XM_017028937.2	c.644C>A	p.Pro215Gln	missense_variant	Exon 5 of 11		XP_016884426.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALG12	ENST00000330817.11	c.644C>A	p.Pro215Gln	missense_variant	Exon 5 of 10	1	NM_024105.4	ENSP00000333813.5
ALG12	ENST00000492791.1	n.173C>A		non_coding_transcript_exon_variant	Exon 1 of 6	3		ENSP00000417387.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461756 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 727172

Gnomad4 AFR exome AF: 0.0000299

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.030
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.54	D
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Uncertain	-0.10	T
MutationAssessor	Uncertain	2.6	M
PrimateAI	Benign	0.45	T
PROVEAN	Pathogenic	-6.9	D
REVEL	Uncertain	0.37
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.017	D
Polyphen		1.0	D
Vest4		0.80
MutPred		0.63		Gain of catalytic residue at P215 (P = 0.0155);
MVP		0.76
MPC		0.63
ClinPred		0.99	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.85
gMVP		0.79

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: rs777173365; hg19: chr22-50303562;