chr22-49909867-A-C

Variant names:

• chr22-49909867-A-C
• rs9616367
• NM_024105.4:c.664+27T>G

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+27T>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 1,612,502 control chromosomes in the GnomAD database, including 40,056 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.24 (4925 hom., cov: 34)
  • Exomes 𝑓: 0.21 (35131 hom.)
• Consequence: ALG12 NM_024105.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.923
• Publications: 16 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=-0.8).
• BP6: Variant 22-49909867-A-C is Benign according to our data. Variant chr22-49909867-A-C is described in ClinVar as Benign. ClinVar VariationId is 261687.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.38 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024105.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALG12	NM_024105.4	MANE Select	c.664+27T>G		intron	N/A	NP_077010.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALG12	ENST00000330817.11	TSL:1 MANE Select	c.664+27T>G		intron	N/A	ENSP00000333813.5
	ALG12	ENST00000492791.1	TSL:3	n.193+27T>G		intron	N/A	ENSP00000417387.1

Frequencies

GnomAD3 genomes AF: 0.241 AC: 36645 AN: 152210 Hom.: 4911 Cov.: 34

Gnomad AFR AF: 0.352

Gnomad AMI AF: 0.391

Gnomad AMR AF: 0.169

Gnomad ASJ AF: 0.289

Gnomad EAS AF: 0.0911

Gnomad SAS AF: 0.395

Gnomad FIN AF: 0.159

Gnomad MID AF: 0.250

Gnomad NFE AF: 0.199

Gnomad OTH AF: 0.214

GnomAD2 exomes AF: 0.215 AC: 53840 AN: 250526 AF XY: 0.225

Gnomad AFR exome AF: 0.359

Gnomad AMR exome AF: 0.122

Gnomad ASJ exome AF: 0.289

Gnomad EAS exome AF: 0.0825

Gnomad FIN exome AF: 0.156

Gnomad NFE exome AF: 0.197

Gnomad OTH exome AF: 0.205

GnomAD4 exome AF: 0.209 AC: 305269 AN: 1460174 Hom.: 35131 Cov.: 33 AF XY: 0.216 AC XY: 156578 AN XY: 726498

African (AFR) AF: 0.366 AC: 12222 AN: 33418

American (AMR) AF: 0.128 AC: 5719 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.282 AC: 7367 AN: 26118

East Asian (EAS) AF: 0.0918 AC: 3644 AN: 39674

South Asian (SAS) AF: 0.410 AC: 35350 AN: 86190

European-Finnish (FIN) AF: 0.161 AC: 8581 AN: 53252

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

European-Non Finnish (NFE) AF: 0.196 AC: 217601 AN: 1110730

Other (OTH) AF: 0.219 AC: 13203 AN: 60312

GnomAD4 genome AF: 0.241 AC: 36694 AN: 152328 Hom.: 4925 Cov.: 34 AF XY: 0.239 AC XY: 17787 AN XY: 74486

African (AFR) AF: 0.352 AC: 14623 AN: 41560

American (AMR) AF: 0.169 AC: 2591 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.289 AC: 1002 AN: 3472

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

South Asian (SAS) AF: 0.395 AC: 1906 AN: 4828

European-Finnish (FIN) AF: 0.159 AC: 1685 AN: 10622

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

European-Non Finnish (NFE) AF: 0.199 AC: 13528 AN: 68024

Other (OTH) AF: 0.219 AC: 463 AN: 2114

Alfa AF: 0.224 Hom.: 1346

Bravo AF: 0.239

Asia WGS AF: 0.277 AC: 965 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Oct 16, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	3.2
DANN	Benign	0.80
PhyloP100		0.92
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	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: rs9616367; hg19: chr22-50303515; COSMIC: COSV58206596; COSMIC: COSV58206596;