NM_000528.4:c.2267+8dupG

Variant names:

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6BS1BS2

The NM_000528.4(MAN2B1):c.2267+8dupG variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00805 in 1,535,290 control chromosomes in the GnomAD database, including 61 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0052 ( 3 hom., cov: 28)

Exomes 𝑓: 0.0083 ( 58 hom. )

Consequence

MAN2B1
NM_000528.4 splice_region, intron

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:4

Conservation

PhyloP100: 0.840

Variant links:

Genes affected

MAN2B1 (HGNC:6826): (mannosidase alpha class 2B member 1) This gene encodes an enzyme that hydrolyzes terminal, non-reducing alpha-D-mannose residues in alpha-D-mannosides. Its activity is necessary for the catabolism of N-linked carbohydrates released during glycoprotein turnover and it is member of family 38 of glycosyl hydrolases. The full length protein is processed in two steps. First, a 49 aa leader sequence is cleaved off and the remainder of the protein is processed into 3 peptides of 70 kDa, 42 kDa (D) and 13/15 kDa (E). Next, the 70 kDa peptide is further processed into three peptides (A, B and C). The A, B and C peptides are disulfide-linked. Defects in this gene have been associated with lysosomal alpha-mannosidosis. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Mar 2010]

MAN2B1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP6

Variant 19-12649904-A-AC is Benign according to our data. Variant chr19-12649904-A-AC is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 290029.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=1, Uncertain_significance=2}.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00524 (702/133926) while in subpopulation NFE AF= 0.00917 (569/62074). AF 95% confidence interval is 0.00854. There are 3 homozygotes in gnomad4. There are 303 alleles in male gnomad4 subpopulation. Median coverage is 28. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
MAN2B1	NM_000528.4 link	c.2267+8dupG	splice_region_variant, intron_variant	Intron 18 of 23	ENST00000456935.7	NP_000519.2	O00754-1
MAN2B1	NM_001173498.2 link	c.2264+8dupG	splice_region_variant, intron_variant	Intron 18 of 23		NP_001166969.1	O00754-2A8K6A7
MAN2B1	XM_005259913.3 link	c.2270+8dupG	splice_region_variant, intron_variant	Intron 18 of 23		XP_005259970.1
MAN2B1	XM_047438841.1 link	c.1166+8dupG	splice_region_variant, intron_variant	Intron 11 of 16		XP_047294797.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
MAN2B1	ENST00000456935.7 link	c.2267+8_2267+9insG	splice_region_variant, intron_variant	Intron 18 of 23	1	NM_000528.4	ENSP00000395473.2	O00754-1
MAN2B1	ENST00000221363.8 link	c.2264+8_2264+9insG	splice_region_variant, intron_variant	Intron 18 of 23	1		ENSP00000221363.4	O00754-2
MAN2B1	ENST00000466794.5 link	n.2857+8_2857+9insG	splice_region_variant, intron_variant	Intron 16 of 21	2

Frequencies

GnomAD3 genomes

AF:

0.00524

AC:

702

AN:

133860

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00181

Gnomad AMI

AF:

0.00363

Gnomad AMR

AF:

0.00332

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000405

Gnomad SAS

AF:

0.000469

Gnomad FIN

AF:

0.000837

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00917

Gnomad OTH

AF:

0.00681

GnomAD3 exomes

AF:

0.00414

AC:

1040

AN:

251360

Hom.:

AF XY:

0.00423

AC XY:

575

AN XY:

135838

show subpopulations

Gnomad AFR exome

AF:

0.00129

Gnomad AMR exome

AF:

0.00200

Gnomad ASJ exome

AF:

0.000893

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00163

Gnomad FIN exome

AF:

0.000693

Gnomad NFE exome

AF:

0.00740

Gnomad OTH exome

AF:

0.00570

GnomAD4 exome

AF:

0.00832

AC:

11658

AN:

1401364

Hom.:

Cov.:

AF XY:

0.00790

AC XY:

5520

AN XY:

698422

show subpopulations

Gnomad4 AFR exome

AF:

0.00131

Gnomad4 AMR exome

AF:

0.00248

Gnomad4 ASJ exome

AF:

0.000944

Gnomad4 EAS exome

AF:

0.0000263

Gnomad4 SAS exome

AF:

0.00163

Gnomad4 FIN exome

AF:

0.00112

Gnomad4 NFE exome

AF:

0.0102

Gnomad4 OTH exome

AF:

0.00801

GnomAD4 genome

AF:

0.00524

AC:

702

AN:

133926

Hom.:

Cov.:

AF XY:

0.00467

AC XY:

303

AN XY:

64872

show subpopulations

Gnomad4 AFR

AF:

0.00180

Gnomad4 AMR

AF:

0.00332

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000405

Gnomad4 SAS

AF:

0.000471

Gnomad4 FIN

AF:

0.000837

Gnomad4 NFE

AF:

0.00917

Gnomad4 OTH

AF:

0.00673

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00824

EpiControl

AF:

0.00901

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Deficiency of alpha-mannosidase

Uncertain:1Benign:2

Jun 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Uncertain:1Benign:1

Sep 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MAN2B1: BS1, BS2 -

May 11, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:1

Aug 12, 2016

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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