22-49907828-T-C

Variant names:

• chr22-49907828-T-C
• rs8135963
• NM_024105.4:c.885A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_024105.4(ALG12):​c.885A>G​(p.Ala295Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.241 in 1,613,820 control chromosomes in the GnomAD database, including 59,745 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.36 (13919 hom., cov: 32)
  • Exomes 𝑓: 0.23 (45826 hom.)
• Consequence: ALG12 NM_024105.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -5.39
• Publications: 31 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: ClinGen, Orphanet, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.002).
• BP6: Variant 22-49907828-T-C is Benign according to our data. Variant chr22-49907828-T-C is described in ClinVar as Benign. ClinVar VariationId is 96102.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-5.39 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.723 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALG12	NM_024105.4	MANE Select	c.885A>G	p.Ala295Ala	synonymous	Exon 7 of 10	NP_077010.1	Q9BV10

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALG12	ENST00000330817.11	TSL:1 MANE Select	c.885A>G	p.Ala295Ala	synonymous	Exon 7 of 10	ENSP00000333813.5	Q9BV10
	ALG12	ENST00000905517.1		c.885A>G	p.Ala295Ala	synonymous	Exon 7 of 10	ENSP00000575576.1
	ALG12	ENST00000905518.1		c.885A>G	p.Ala295Ala	synonymous	Exon 7 of 10	ENSP00000575577.1

Frequencies

GnomAD3 genomes AF: 0.358 AC: 54348 AN: 151950 Hom.: 13859 Cov.: 32

Gnomad AFR AF: 0.729

Gnomad AMI AF: 0.468

Gnomad AMR AF: 0.223

Gnomad ASJ AF: 0.303

Gnomad EAS AF: 0.146

Gnomad SAS AF: 0.411

Gnomad FIN AF: 0.167

Gnomad MID AF: 0.294

Gnomad NFE AF: 0.207

Gnomad OTH AF: 0.306

GnomAD2 exomes AF: 0.256 AC: 64213 AN: 251256 AF XY: 0.258

Gnomad AFR exome AF: 0.742

Gnomad AMR exome AF: 0.152

Gnomad ASJ exome AF: 0.305

Gnomad EAS exome AF: 0.134

Gnomad FIN exome AF: 0.165

Gnomad NFE exome AF: 0.205

Gnomad OTH exome AF: 0.233

GnomAD4 exome AF: 0.229 AC: 334278 AN: 1461752 Hom.: 45826 Cov.: 37 AF XY: 0.234 AC XY: 170123 AN XY: 727166

African (AFR) AF: 0.753 AC: 25209 AN: 33480

American (AMR) AF: 0.160 AC: 7163 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.297 AC: 7766 AN: 26132

East Asian (EAS) AF: 0.138 AC: 5459 AN: 39678

South Asian (SAS) AF: 0.425 AC: 36635 AN: 86256

European-Finnish (FIN) AF: 0.169 AC: 8997 AN: 53330

Middle Eastern (MID) AF: 0.327 AC: 1888 AN: 5768

European-Non Finnish (NFE) AF: 0.203 AC: 225718 AN: 1111996

Other (OTH) AF: 0.256 AC: 15443 AN: 60388

GnomAD4 genome AF: 0.358 AC: 54463 AN: 152068 Hom.: 13919 Cov.: 32 AF XY: 0.354 AC XY: 26284 AN XY: 74328

African (AFR) AF: 0.729 AC: 30252 AN: 41474

American (AMR) AF: 0.223 AC: 3408 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.303 AC: 1051 AN: 3466

East Asian (EAS) AF: 0.146 AC: 753 AN: 5162

South Asian (SAS) AF: 0.410 AC: 1976 AN: 4814

European-Finnish (FIN) AF: 0.167 AC: 1769 AN: 10580

Middle Eastern (MID) AF: 0.279 AC: 82 AN: 294

European-Non Finnish (NFE) AF: 0.207 AC: 14089 AN: 67964

Other (OTH) AF: 0.310 AC: 657 AN: 2116

Alfa AF: 0.251 Hom.: 10289

Bravo AF: 0.370

Asia WGS AF: 0.331 AC: 1152 AN: 3476

EpiCase AF: 0.204

EpiControl AF: 0.211

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	ALG12-congenital disorder of glycosylation (2)
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.16
DANN	Benign	0.24
PhyloP100		-5.4
PromoterAI		-0.0051	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs8135963; hg19: chr22-50301476; COSMIC: COSV58207567; COSMIC: COSV58207567;