Genetic Variant ALG1L2:p.Arg69Cys (chr3-130092174-C-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001136152.1(ALG1L2):c.205C>T(p.Arg69Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00701 in 1,612,912 control chromosomes in the GnomAD database, including 48 homozygotes. In-silico tool predicts a benign outcome for this variant. 9/13 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0046 ( 4 hom., cov: 33)

Exomes 𝑓: 0.0073 ( 44 hom. )

Consequence

ALG1L2
NM_001136152.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.395

Variant links:

Genes affected

ALG1L2 (HGNC:37258): (ALG1 chitobiosyldiphosphodolichol beta-mannosyltransferase like 2) Predicted to enable mannosyltransferase activity. Predicted to be involved in protein glycosylation. Predicted to be active in endoplasmic reticulum. [provided by Alliance of Genome Resources, Apr 2022]

ALG1L2 links:

LINC02014 (HGNC:52849): (long intergenic non-protein coding RNA 2014)

LINC02014 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0076847076).

BS2

High Homozygotes in GnomAd4 at 4 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALG1L2	NM_001136152.1 link	c.205C>T	p.Arg69Cys	missense_variant	Exon 3 of 8	ENST00000425059.1	NP_001129624.1	C9J202
LINC02014	NR_146710.1 link	n.158-307G>A		intron_variant	Intron 1 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALG1L2	ENST00000425059.1 link	c.205C>T	p.Arg69Cys	missense_variant	Exon 3 of 8	5	NM_001136152.1	ENSP00000479850.1		C9J202

Frequencies

GnomAD3 genomes

AF:

0.00462

AC:

703

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00123

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00203

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000413

Gnomad FIN

AF:

0.00546

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00800

Gnomad OTH

AF:

0.00334

GnomAD3 exomes

AF:

0.00470

AC:

1167

AN:

248092

Hom.:

AF XY:

0.00489

AC XY:

659

AN XY:

134776

show subpopulations

Gnomad AFR exome

AF:

0.00123

Gnomad AMR exome

AF:

0.00134

Gnomad ASJ exome

AF:

0.00220

Gnomad EAS exome

AF:

0.000164

Gnomad SAS exome

AF:

0.000787

Gnomad FIN exome

AF:

0.00543

Gnomad NFE exome

AF:

0.00816

Gnomad OTH exome

AF:

0.00396

GnomAD4 exome

AF:

0.00726

AC:

10611

AN:

1460582

Hom.:

Cov.:

AF XY:

0.00711

AC XY:

5165

AN XY:

726592

show subpopulations

Gnomad4 AFR exome

AF:

0.00117

Gnomad4 AMR exome

AF:

0.00148

Gnomad4 ASJ exome

AF:

0.00172

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000894

Gnomad4 FIN exome

AF:

0.00539

Gnomad4 NFE exome

AF:

0.00877

Gnomad4 OTH exome

AF:

0.00569

GnomAD4 genome

AF:

0.00461

AC:

703

AN:

152330

Hom.:

Cov.:

AF XY:

0.00431

AC XY:

321

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.00123

Gnomad4 AMR

AF:

0.00203

Gnomad4 ASJ

AF:

0.00144

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00546

Gnomad4 NFE

AF:

0.00800

Gnomad4 OTH

AF:

0.00331

Alfa

AF:

0.00631

Hom.:

Bravo

AF:

0.00430

TwinsUK

AF:

0.00647

AC:

ALSPAC

AF:

0.00804

AC:

ESP6500AA

AF:

0.000723

AC:

ESP6500EA

AF:

0.00943

AC:

ExAC

AF:

0.00525

AC:

637

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 10, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.205C>T (p.R69C) alteration is located in exon 3 (coding exon 3) of the ALG1L2 gene. This alteration results from a C to T substitution at nucleotide position 205, causing the arginine (R) at amino acid position 69 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.38

CADD

Benign

DANN

Benign

0.52

DEOGEN2

Benign

0.054

FATHMM_MKL

Benign

0.019

LIST_S2

Benign

0.20

MetaRNN

Benign

0.0077

MutationAssessor

Uncertain

2.3

PrimateAI

Benign

0.38

Sift4G

Benign

0.17

Polyphen

0.017

Vest4

0.13

MVP

0.22

GERP RS

1.2

Varity_R

0.13

gMVP

0.55

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