rs144665682

Positions:

chr22-49909927-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000330817.11(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 (★★). 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
ENST00000330817.11 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 2.17

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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
ALG12	NM_024105.4 linkuse as main transcript	c.631C>T	p.Arg211Cys	missense_variant	5/10	ENST00000330817.11	NP_077010.1
ALG12	XM_017028936.2 linkuse as main transcript	c.631C>T	p.Arg211Cys	missense_variant	5/10		XP_016884425.1
ALG12	XM_017028937.2 linkuse as main transcript	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 linkuse as main transcript	c.631C>T	p.Arg211Cys	missense_variant	5/10	1	NM_024105.4	ENSP00000333813	P1
ALG12	ENST00000492791.1 linkuse as main transcript	c.163C>T	p.Arg55Cys	missense_variant, NMD_transcript_variant	1/6	3		ENSP00000417387

Frequencies

GnomAD3 genomes

AF:

0.00614

AC:

935

AN:

152252

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.0101

AC XY:

1368

AN XY:

135784

show subpopulations

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.:

AF XY:

0.00765

AC XY:

5561

AN XY:

727172

show subpopulations

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.:

Cov.:

AF XY:

0.00643

AC XY:

479

AN XY:

74510

show subpopulations

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.:

Bravo

AF:

0.00545

TwinsUK

AF:

0.00512

AC:

ALSPAC

AF:

0.00545

AC:

ESP6500AA

AF:

0.00409

AC:

ESP6500EA

AF:

0.00442

AC:

ExAC

AF:

0.00944

AC:

1146

Asia WGS

AF:

0.0280

AC:

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

LINK: link

Submissions by phenotype

not provided

Benign:5

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 12, 2022	See Variant Classification Assertion Criteria. -
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, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

ALG12-congenital disorder of glycosylation

Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

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

BayesDel_noAF

Benign

-0.35

CADD

Benign

DANN

Benign

0.92

DEOGEN2

Benign

0.35

Eigen

Benign

-0.90

Eigen_PC

Benign

-0.99

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.61

MetaRNN

Benign

0.0062

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.80

MutationTaster

Benign

1.0

PrimateAI

Benign

0.24

PROVEAN

Uncertain

-2.8

REVEL

Benign

0.24

Sift

Benign

0.17

Sift4G

Benign

0.17

Polyphen

0.019

Vest4

0.19

MVP

0.63

MPC

0.22

ClinPred

0.0095

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over