rs76707654

Variant names:

• chr22-49913667-C-T
• rs76707654
• NM_024105.4:c.99G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_024105.4(ALG12):​c.99G>A​(p.Val33Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0167 in 1,614,138 control chromosomes in the GnomAD database, including 738 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.042 (302 hom., cov: 33)
  • Exomes 𝑓: 0.014 (436 hom.)
• Consequence: ALG12 NM_024105.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.378
• Publications: 5 publications found

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]

ALG12 Gene-Disease associations (from GenCC):

• ALG12-congenital disorder of glycosylation

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, G2P, ClinGen, Labcorp Genetics (formerly Invitae), PanelApp Australia, Orphanet

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP6: Variant 22-49913667-C-T is Benign according to our data. Variant chr22-49913667-C-T is described in ClinVar as Benign. ClinVar VariationId is 342060.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.378 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.116 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALG12	NM_024105.4	c.99G>A	p.Val33Val	synonymous_variant	Exon 2 of 10	ENST00000330817.11	NP_077010.1
ALG12	XM_017028936.2	c.99G>A	p.Val33Val	synonymous_variant	Exon 2 of 10		XP_016884425.1
ALG12	XM_017028937.2	c.99G>A	p.Val33Val	synonymous_variant	Exon 2 of 11		XP_016884426.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALG12	ENST00000330817.11	c.99G>A	p.Val33Val	synonymous_variant	Exon 2 of 10	1	NM_024105.4	ENSP00000333813.5

Frequencies

GnomAD3 genomes AF: 0.0414 AC: 6307 AN: 152200 Hom.: 302 Cov.: 33

Gnomad AFR AF: 0.119

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0180

Gnomad ASJ AF: 0.0173

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0273

Gnomad FIN AF: 0.00245

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0120

Gnomad OTH AF: 0.0349

GnomAD2 exomes AF: 0.0193 AC: 4855 AN: 251366 AF XY: 0.0180

Gnomad AFR exome AF: 0.124

Gnomad AMR exome AF: 0.0105

Gnomad ASJ exome AF: 0.0134

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00212

Gnomad NFE exome AF: 0.0118

Gnomad OTH exome AF: 0.0142

GnomAD4 exome AF: 0.0142 AC: 20710 AN: 1461820 Hom.: 436 Cov.: 33 AF XY: 0.0144 AC XY: 10437 AN XY: 727208

African (AFR) AF: 0.125 AC: 4200 AN: 33480

American (AMR) AF: 0.0115 AC: 513 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0117 AC: 306 AN: 26136

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39698

South Asian (SAS) AF: 0.0293 AC: 2526 AN: 86258

European-Finnish (FIN) AF: 0.00236 AC: 126 AN: 53356

Middle Eastern (MID) AF: 0.0298 AC: 172 AN: 5768

European-Non Finnish (NFE) AF: 0.0106 AC: 11733 AN: 1112008

Other (OTH) AF: 0.0187 AC: 1130 AN: 60392

GnomAD4 genome AF: 0.0415 AC: 6324 AN: 152318 Hom.: 302 Cov.: 33 AF XY: 0.0407 AC XY: 3031 AN XY: 74484

African (AFR) AF: 0.119 AC: 4931 AN: 41554

American (AMR) AF: 0.0180 AC: 275 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0173 AC: 60 AN: 3472

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5182

South Asian (SAS) AF: 0.0273 AC: 132 AN: 4834

European-Finnish (FIN) AF: 0.00245 AC: 26 AN: 10622

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0120 AC: 816 AN: 68034

Other (OTH) AF: 0.0345 AC: 73 AN: 2114

Alfa AF: 0.0260 Hom.: 56

Bravo AF: 0.0464

Asia WGS AF: 0.0210 AC: 73 AN: 3478

EpiCase AF: 0.0106

EpiControl AF: 0.0132

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jan 06, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

ALG12-congenital disorder of glycosylation Benign:2

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	8.1
DANN	Benign	0.77
PhyloP100		0.38
Mutation Taster		=96/4	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs76707654; hg19: chr22-50307315;