rs144665682

Variant names:

• chr22-49909927-G-A
• rs144665682
• NM_024105.4:c.631C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_024105.4(ALG12):​c.631C>T​(p.Arg211Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0068 in 1,614,130 control chromosomes in the GnomAD database, including 123 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. R211R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0062 (12 hom., cov: 33)
  • Exomes 𝑓: 0.0069 (111 hom.)
• Consequence: ALG12 NM_024105.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 2.17
• Publications: 12 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006156057).
• BP6: Variant 22-49909927-G-A is Benign according to our data. Variant chr22-49909927-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 96097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00616 (938/152370) while in subpopulation EAS AF = 0.0324 (168/5186). AF 95% confidence interval is 0.0284. There are 12 homozygotes in GnomAd4. There are 479 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 12 AR gene

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.631C>T	p.Arg211Cys	missense	Exon 5 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.631C>T	p.Arg211Cys	missense	Exon 5 of 10	ENSP00000333813.5	Q9BV10
	ALG12	ENST00000905517.1		c.631C>T	p.Arg211Cys	missense	Exon 5 of 10	ENSP00000575576.1
	ALG12	ENST00000905518.1		c.631C>T	p.Arg211Cys	missense	Exon 5 of 10	ENSP00000575577.1

Frequencies

GnomAD3 genomes AF: 0.00614 AC: 935 AN: 152252 Hom.: 12 Cov.: 33

Gnomad AFR AF: 0.00588

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00321

Gnomad ASJ AF: 0.00518

Gnomad EAS AF: 0.0323

Gnomad SAS AF: 0.0312

Gnomad FIN AF: 0.00132

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00416

Gnomad OTH AF: 0.00334

GnomAD2 exomes AF: 0.00904 AC: 2271 AN: 251096 AF XY: 0.0101

Gnomad AFR exome AF: 0.00468

Gnomad AMR exome AF: 0.00200

Gnomad ASJ exome AF: 0.00517

Gnomad EAS exome AF: 0.0279

Gnomad FIN exome AF: 0.00171

Gnomad NFE exome AF: 0.00452

Gnomad OTH exome AF: 0.00588

GnomAD4 exome AF: 0.00687 AC: 10037 AN: 1461760 Hom.: 111 Cov.: 34 AF XY: 0.00765 AC XY: 5561 AN XY: 727172

African (AFR) AF: 0.00609 AC: 204 AN: 33480

American (AMR) AF: 0.00190 AC: 85 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00497 AC: 130 AN: 26136

East Asian (EAS) AF: 0.0300 AC: 1189 AN: 39698

South Asian (SAS) AF: 0.0309 AC: 2668 AN: 86254

European-Finnish (FIN) AF: 0.00191 AC: 102 AN: 53320

Middle Eastern (MID) AF: 0.00867 AC: 50 AN: 5768

European-Non Finnish (NFE) AF: 0.00462 AC: 5140 AN: 1111988

Other (OTH) AF: 0.00777 AC: 469 AN: 60392

GnomAD4 genome AF: 0.00616 AC: 938 AN: 152370 Hom.: 12 Cov.: 33 AF XY: 0.00643 AC XY: 479 AN XY: 74510

African (AFR) AF: 0.00594 AC: 247 AN: 41586

American (AMR) AF: 0.00320 AC: 49 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00518 AC: 18 AN: 3472

East Asian (EAS) AF: 0.0324 AC: 168 AN: 5186

South Asian (SAS) AF: 0.0313 AC: 151 AN: 4830

European-Finnish (FIN) AF: 0.00132 AC: 14 AN: 10624

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00416 AC: 283 AN: 68044

Other (OTH) AF: 0.00331 AC: 7 AN: 2116

Alfa AF: 0.00581 Hom.: 13

Bravo AF: 0.00545

TwinsUK AF: 0.00512 AC: 19

ALSPAC AF: 0.00545 AC: 21

ESP6500AA AF: 0.00409 AC: 18

ESP6500EA AF: 0.00442 AC: 38

ExAC AF: 0.00944 AC: 1146

Asia WGS AF: 0.0280 AC: 97 AN: 3478

EpiCase AF: 0.00567

EpiControl AF: 0.00462

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	2	ALG12-congenital disorder of glycosylation (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	15
DANN	Benign	0.92
DEOGEN2	Benign	0.35	T
Eigen	Benign	-0.90
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.61	T
MetaRNN	Benign	0.0062	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.80	N
PhyloP100		2.2
PrimateAI	Benign	0.24	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.24
Sift	Benign	0.17	T
Sift4G	Benign	0.17	T
Polyphen		0.019	B
Vest4		0.19
MVP		0.63
MPC		0.22
ClinPred		0.0095	T
GERP RS		-2.9
Varity_R		0.099
gMVP		0.49
Mutation Taster		=99/1	polymorphism

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: rs144665682; hg19: chr22-50303575; COSMIC: COSV58208071; COSMIC: COSV58208071;