rs9616368

Variant names:

• chr22-49909885-C-G
• rs9616368
• NM_024105.4:c.664+9G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_024105.4(ALG12):​c.664+9G>C 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 1,613,232 control chromosomes in the GnomAD database, including 39,979 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 (35115 hom.)
• Consequence: ALG12 NM_024105.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.205
• Publications: 17 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 22-49909885-C-G is Benign according to our data. Variant chr22-49909885-C-G is described in ClinVar as [Benign]. Clinvar id is 96099.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.379 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALG12	NM_024105.4	c.664+9G>C		intron_variant	Intron 5 of 9	ENST00000330817.11	NP_077010.1
ALG12	XM_017028936.2	c.664+9G>C		intron_variant	Intron 5 of 9		XP_016884425.1
ALG12	XM_017028937.2	c.664+9G>C		intron_variant	Intron 5 of 10		XP_016884426.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALG12	ENST00000330817.11	c.664+9G>C		intron_variant	Intron 5 of 9	1	NM_024105.4	ENSP00000333813.5
ALG12	ENST00000492791.1	n.193+9G>C		intron_variant	Intron 1 of 5	3		ENSP00000417387.1

Frequencies

GnomAD3 genomes AF: 0.240 AC: 36530 AN: 152068 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: 0.0911

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

GnomAD2 exomes AF: 0.215 AC: 53811 AN: 250768 AF XY: 0.225

Gnomad AFR exome AF: 0.358

Gnomad AMR exome AF: 0.122

Gnomad ASJ exome AF: 0.289

Gnomad EAS exome AF: 0.0824

Gnomad FIN exome AF: 0.156

Gnomad NFE exome AF: 0.196

Gnomad OTH exome AF: 0.205

GnomAD4 exome AF: 0.209 AC: 305664 AN: 1461048 Hom.: 35115 Cov.: 35 AF XY: 0.216 AC XY: 156706 AN XY: 726820

African (AFR) AF: 0.366 AC: 12242 AN: 33462

American (AMR) AF: 0.128 AC: 5720 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.282 AC: 7372 AN: 26126

East Asian (EAS) AF: 0.0919 AC: 3648 AN: 39678

South Asian (SAS) AF: 0.410 AC: 35329 AN: 86226

European-Finnish (FIN) AF: 0.161 AC: 8588 AN: 53280

Middle Eastern (MID) AF: 0.274 AC: 1582 AN: 5768

European-Non Finnish (NFE) AF: 0.196 AC: 217966 AN: 1111436

Other (OTH) AF: 0.219 AC: 13217 AN: 60356

GnomAD4 genome AF: 0.240 AC: 36577 AN: 152184 Hom.: 4864 Cov.: 34 AF XY: 0.238 AC XY: 17739 AN XY: 74420

African (AFR) AF: 0.351 AC: 14562 AN: 41486

American (AMR) AF: 0.169 AC: 2588 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.287 AC: 996 AN: 3466

East Asian (EAS) AF: 0.0908 AC: 471 AN: 5190

South Asian (SAS) AF: 0.393 AC: 1898 AN: 4826

European-Finnish (FIN) AF: 0.158 AC: 1676 AN: 10606

Middle Eastern (MID) AF: 0.231 AC: 68 AN: 294

European-Non Finnish (NFE) AF: 0.199 AC: 13503 AN: 67990

Other (OTH) AF: 0.218 AC: 461 AN: 2112

Alfa AF: 0.219 Hom.: 1252

Bravo AF: 0.239

Asia WGS AF: 0.277 AC: 964 AN: 3478

EpiCase AF: 0.194

EpiControl AF: 0.200

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 10, 2012

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

ALG12-congenital disorder of glycosylation Benign:2

Jan 13, 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

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.2
DANN	Benign	0.33
PhyloP100		-0.20
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs9616368; hg19: chr22-50303533;