rs144665682

Positions:

• chr22-49909927-G-A

Variant summary

Our verdict is Benign. Variant got -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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar 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

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]

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 96097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-49909927-G-A is described in Lovd as [Likely_benign].
• 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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALG12	NM_024105.4	c.631C>T	p.Arg211Cys	missense_variant	5/10	ENST00000330817.11	NP_077010.1
ALG12	XM_017028936.2	c.631C>T	p.Arg211Cys	missense_variant	5/10		XP_016884425.1
ALG12	XM_017028937.2	c.631C>T	p.Arg211Cys	missense_variant	5/11		XP_016884426.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALG12	ENST00000330817.11	c.631C>T	p.Arg211Cys	missense_variant	5/10	1	NM_024105.4	ENSP00000333813.5
ALG12	ENST00000492791.1	n.160C>T		non_coding_transcript_exon_variant	1/6	3		ENSP00000417387.1

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

GnomAD3 exomes AF: 0.00904 AC: 2271 AN: 251096 Hom.: 33 AF XY: 0.0101 AC XY: 1368 AN XY: 135784

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 SAS exome AF: 0.0319

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

Gnomad4 AFR exome AF: 0.00609

Gnomad4 AMR exome AF: 0.00190

Gnomad4 ASJ exome AF: 0.00497

Gnomad4 EAS exome AF: 0.0300

Gnomad4 SAS exome AF: 0.0309

Gnomad4 FIN exome AF: 0.00191

Gnomad4 NFE exome AF: 0.00462

Gnomad4 OTH exome AF: 0.00777

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

Gnomad4 AFR AF: 0.00594

Gnomad4 AMR AF: 0.00320

Gnomad4 ASJ AF: 0.00518

Gnomad4 EAS AF: 0.0324

Gnomad4 SAS AF: 0.0313

Gnomad4 FIN AF: 0.00132

Gnomad4 NFE AF: 0.00416

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00562 Hom.: 6

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

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 05, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 12, 2022	See Variant Classification Assertion Criteria. -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

ALG12-congenital disorder of glycosylation Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jul 30, 2013

- -

Computational scores

Source: dbNSFP v4.3

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
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

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

Publications

LitVar

Other links and lift over

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