Genetic Variant ALG10B:p.Leu253Trp (chr12-38320549-T-G) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_001013620.4(ALG10B):c.758T>G(p.Leu253Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00391 in 1,614,158 control chromosomes in the GnomAD database, including 35 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0035 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0040 ( 33 hom. )

Consequence

ALG10B
NM_001013620.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 3.38

Variant links:

Genes affected

ALG10B (HGNC:31088): (ALG10 alpha-1,2-glucosyltransferase B) Enables transferase activity. Involved in positive regulation of inward rectifier potassium channel activity; positive regulation of protein glycosylation; and protein glycosylation. Located in endoplasmic reticulum. Implicated in long QT syndrome 2. [provided by Alliance of Genome Resources, Apr 2022]

ALG10B links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011118591).

BP6

Variant 12-38320549-T-G is Benign according to our data. Variant chr12-38320549-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 2642845.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00396 (5785/1461824) while in subpopulation MID AF= 0.0362 (209/5768). AF 95% confidence interval is 0.0322. There are 33 homozygotes in gnomad4_exome. There are 2982 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALG10B	NM_001013620.4 link	c.758T>G	p.Leu253Trp	missense_variant	Exon 3 of 3	ENST00000308742.9	NP_001013642.2	Q5I7T1
ALG10B	XM_005268665.5 link	c.578T>G	p.Leu193Trp	missense_variant	Exon 3 of 3		XP_005268722.1
ALG10B	NM_001308340.2 link	c.369+2091T>G		intron_variant	Intron 2 of 2		NP_001295269.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALG10B	ENST00000308742.9 link	c.758T>G	p.Leu253Trp	missense_variant	Exon 3 of 3	1	NM_001013620.4	ENSP00000310120.4		Q5I7T1

Frequencies

GnomAD3 genomes

AF:

0.00351

AC:

535

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00681

Gnomad ASJ

AF:

0.00576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00331

Gnomad FIN

AF:

0.00141

Gnomad MID

AF:

0.0380

Gnomad NFE

AF:

0.00478

Gnomad OTH

AF:

0.00623

GnomAD3 exomes

AF:

0.00418

AC:

1051

AN:

251414

Hom.:

AF XY:

0.00456

AC XY:

619

AN XY:

135872

show subpopulations

Gnomad AFR exome

AF:

0.000369

Gnomad AMR exome

AF:

0.00593

Gnomad ASJ exome

AF:

0.00615

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00441

Gnomad FIN exome

AF:

0.00129

Gnomad NFE exome

AF:

0.00492

Gnomad OTH exome

AF:

0.00897

GnomAD4 exome

AF:

0.00396

AC:

5785

AN:

1461824

Hom.:

Cov.:

AF XY:

0.00410

AC XY:

2982

AN XY:

727206

show subpopulations

Gnomad4 AFR exome

AF:

0.000807

Gnomad4 AMR exome

AF:

0.00586

Gnomad4 ASJ exome

AF:

0.00704

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00412

Gnomad4 FIN exome

AF:

0.00133

Gnomad4 NFE exome

AF:

0.00393

Gnomad4 OTH exome

AF:

0.00510

GnomAD4 genome

AF:

0.00349

AC:

532

AN:

152334

Hom.:

Cov.:

AF XY:

0.00357

AC XY:

266

AN XY:

74498

show subpopulations

Gnomad4 AFR

AF:

0.000721

Gnomad4 AMR

AF:

0.00680

Gnomad4 ASJ

AF:

0.00576

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00311

Gnomad4 FIN

AF:

0.00141

Gnomad4 NFE

AF:

0.00478

Gnomad4 OTH

AF:

0.00616

Alfa

AF:

0.00460

Hom.:

Bravo

AF:

0.00333

TwinsUK

AF:

0.00351

AC:

ALSPAC

AF:

0.00285

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00570

AC:

ExAC

AF:

0.00423

AC:

514

EpiCase

AF:

0.00622

EpiControl

AF:

0.00480

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

May 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ALG10B: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.34

CADD

Benign

DANN

Benign

0.75

DEOGEN2

Benign

0.011

Eigen

Benign

-0.17

Eigen_PC

Benign

-0.30

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.78

M_CAP

Benign

0.0077

MetaRNN

Benign

0.011

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.6

PrimateAI

Benign

0.41

PROVEAN

Benign

-2.1

REVEL

Benign

0.18

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.026

Polyphen

0.71

Vest4

0.55

MVP

0.40

MPC

0.35

ClinPred

0.036

GERP RS

2.1

Varity_R

0.48

gMVP

0.70

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