Genetic Variant MAN2B1:p.His70Leu (chr19-12665756-T-A) – ACMG Classification: Likely_pathogenic (8 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong

The NM_000528.4(MAN2B1):c.209A>T(p.His70Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,862 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

MAN2B1
NM_000528.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.62

Publications

0 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: ClinGen, Genomics England PanelApp, Myriad Women’s Health, G2P, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)

MAN2B1 links:

ENSG00000269590 (HGNC:):

ENSG00000269590 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 uncertain in NM_000528.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.985

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAN2B1	NM_000528.4 link	c.209A>T	p.His70Leu	missense_variant	Exon 2 of 24	ENST00000456935.7	NP_000519.2	O00754-1
MAN2B1	NM_001440570.1 link	c.209A>T	p.His70Leu	missense_variant	Exon 2 of 24		NP_001427499.1
MAN2B1	NM_001173498.2 link	c.209A>T	p.His70Leu	missense_variant	Exon 2 of 24		NP_001166969.1	O00754-2A8K6A7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAN2B1	ENST00000456935.7 link	c.209A>T	p.His70Leu	missense_variant	Exon 2 of 24	1	NM_000528.4	ENSP00000395473.2		O00754-1
ENSG00000269590	ENST00000597961.1 link	c.200A>T	p.His67Leu	missense_variant	Exon 3 of 5	4		ENSP00000472710.1		M0R2P5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461862

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727242

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53388

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1112012

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.92

BayesDel_addAF

Pathogenic

0.48

BayesDel_noAF

Pathogenic

0.45

CADD

Pathogenic

(source)

DANN

Benign

0.97

DEOGEN2

Pathogenic

0.92

D;.;.;.

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.91

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.93

D;D;D;D

M_CAP

Pathogenic

0.30

MetaRNN

Pathogenic

0.99

D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

3.8

H;H;.;.

PhyloP100

7.6

PrimateAI

Uncertain

0.68

PROVEAN

Pathogenic

-9.8

D;D;.;.

REVEL

Pathogenic

0.94

Sift

Pathogenic

0.0

D;D;.;.

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

1.0

D;.;.;.

Vest4

0.97

MutPred

0.90

Loss of disorder (P = 0.1746);Loss of disorder (P = 0.1746);.;.;

MVP

0.98

MPC

1.7

ClinPred

1.0

GERP RS

5.8

Varity_R

0.97

gMVP

0.98

Mutation Taster

=2/98

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over