rs9616204

Positions:

• chr22-49909882-T-C

Variant summary

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

The NM_024105.4(ALG12):​c.664+12A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.212 in 1,613,118 control chromosomes in the GnomAD database, including 39,987 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.24 (4864 hom., cov: 34)
  • Exomes 𝑓: 0.21 (35123 hom.)
• Consequence: ALG12 NM_024105.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.67

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.03).
• BP6: Variant 22-49909882-T-C is Benign according to our data. Variant chr22-49909882-T-C is described in ClinVar as [Benign]. Clinvar id is 96098.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-49909882-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.378 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALG12	NM_024105.4	c.664+12A>G		intron_variant		ENST00000330817.11	NP_077010.1
ALG12	XM_017028936.2	c.664+12A>G		intron_variant			XP_016884425.1
ALG12	XM_017028937.2	c.664+12A>G		intron_variant			XP_016884426.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALG12	ENST00000330817.11	c.664+12A>G		intron_variant		1	NM_024105.4	ENSP00000333813.5
ALG12	ENST00000492791.1	n.193+12A>G		intron_variant		3		ENSP00000417387.1

Frequencies

GnomAD3 genomes AF: 0.240 AC: 36527 AN: 152076 Hom.: 4851 Cov.: 34

Gnomad AFR AF: 0.351

Gnomad AMI AF: 0.390

Gnomad AMR AF: 0.169

Gnomad ASJ AF: 0.287

Gnomad EAS AF: 0.0912

Gnomad SAS AF: 0.394

Gnomad FIN AF: 0.158

Gnomad MID AF: 0.250

Gnomad NFE AF: 0.199

Gnomad OTH AF: 0.214

GnomAD3 exomes AF: 0.215 AC: 53814 AN: 250762 Hom.: 6843 AF XY: 0.225 AC XY: 30474 AN XY: 135592

Gnomad AFR exome AF: 0.358

Gnomad AMR exome AF: 0.122

Gnomad ASJ exome AF: 0.289

Gnomad EAS exome AF: 0.0825

Gnomad SAS exome AF: 0.410

Gnomad FIN exome AF: 0.156

Gnomad NFE exome AF: 0.196

Gnomad OTH exome AF: 0.205

GnomAD4 exome AF: 0.209 AC: 305606 AN: 1460926 Hom.: 35123 Cov.: 35 AF XY: 0.216 AC XY: 156686 AN XY: 726774

Gnomad4 AFR exome AF: 0.366

Gnomad4 AMR exome AF: 0.128

Gnomad4 ASJ exome AF: 0.282

Gnomad4 EAS exome AF: 0.0919

Gnomad4 SAS exome AF: 0.410

Gnomad4 FIN exome AF: 0.161

Gnomad4 NFE exome AF: 0.196

Gnomad4 OTH exome AF: 0.219

GnomAD4 genome AF: 0.240 AC: 36574 AN: 152192 Hom.: 4864 Cov.: 34 AF XY: 0.238 AC XY: 17737 AN XY: 74434

Gnomad4 AFR AF: 0.351

Gnomad4 AMR AF: 0.169

Gnomad4 ASJ AF: 0.287

Gnomad4 EAS AF: 0.0908

Gnomad4 SAS AF: 0.393

Gnomad4 FIN AF: 0.158

Gnomad4 NFE AF: 0.199

Gnomad4 OTH AF: 0.218

Alfa AF: 0.229 Hom.: 975

Bravo AF: 0.239

Asia WGS AF: 0.277 AC: 964 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 10, 2012	- -

ALG12-congenital disorder of glycosylation Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

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- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.50
DANN	Benign	0.22
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs9616204; hg19: chr22-50303530;