19-12649904-ACC-ACCC

Variant names:

Variant summary

Our verdict is Benign. The variant received -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:5

Conservation

PhyloP100: 0.840

Publications

1 publications found

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 Gene-Disease associations (from GenCC):

alpha-mannosidosis
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Myriad Women's Health, G2P, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), ClinGen, Genomics England PanelApp

MAN2B1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 290029.

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 the male GnomAd4 subpopulation. Median coverage is 28. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000528.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
MAN2B1	NM_000528.4	MANE Select	c.2267+8dupG	splice_region intron	N/A	NP_000519.2	O00754-1
MAN2B1	NM_001440570.1		c.2270+8dupG	splice_region intron	N/A	NP_001427499.1
MAN2B1	NM_001173498.2		c.2264+8dupG	splice_region intron	N/A	NP_001166969.1	O00754-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
MAN2B1	ENST00000456935.7	TSL:1 MANE Select	c.2267+8_2267+9insG	splice_region intron	N/A	ENSP00000395473.2	O00754-1
MAN2B1	ENST00000221363.9	TSL:1	c.2264+8_2264+9insG	splice_region intron	N/A	ENSP00000221363.4	O00754-2
MAN2B1	ENST00000964003.1		c.2315+8_2315+9insG	splice_region intron	N/A	ENSP00000634062.1

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

GnomAD2 exomes

AF:

0.00414

AC:

1040

AN:

251360

AF XY:

0.00423

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 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

African (AFR)

AF:

0.00131

AC:

AN:

32096

American (AMR)

AF:

0.00248

AC:

109

AN:

43888

Ashkenazi Jewish (ASJ)

AF:

0.000944

AC:

AN:

24354

East Asian (EAS)

AF:

0.0000263

AC:

AN:

38070

South Asian (SAS)

AF:

0.00163

AC:

140

AN:

85688

European-Finnish (FIN)

AF:

0.00112

AC:

AN:

49066

Middle Eastern (MID)

AF:

0.000617

AC:

AN:

4860

European-Non Finnish (NFE)

AF:

0.0102

AC:

10826

AN:

1066072

Other (OTH)

AF:

0.00801

AC:

459

AN:

57270

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

515

1031

1546

2062

2577

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

430

860

1290

1720

2150

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00524

AC:

702

AN:

133926

Hom.:

Cov.:

AF XY:

0.00467

AC XY:

303

AN XY:

64872

show subpopulations

African (AFR)

AF:

0.00180

AC:

AN:

34964

American (AMR)

AF:

0.00332

AC:

AN:

13270

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3192

East Asian (EAS)

AF:

0.000405

AC:

AN:

4934

South Asian (SAS)

AF:

0.000471

AC:

AN:

4250

European-Finnish (FIN)

AF:

0.000837

AC:

AN:

8368

Middle Eastern (MID)

AF:

0.00

AC:

AN:

264

European-Non Finnish (NFE)

AF:

0.00917

AC:

569

AN:

62074

Other (OTH)

AF:

0.00673

AC:

AN:

1784

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

109

136

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00187

Hom.:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00824

EpiControl

AF:

0.00901

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Deficiency of alpha-mannosidase (3)

not provided (3)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.84

Mutation Taster

=100/0

polymorphism

(source)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over