19-12657482-G-C

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000528.4(MAN2B1):c.1383C>G(p.Tyr461*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000707 in 1,414,556 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Y461Y) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

MAN2B1
NM_000528.4 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: -0.928

Publications

4 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 19-12657482-G-C is Pathogenic according to our data. Variant chr19-12657482-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 189068.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
MAN2B1	NM_000528.4 link	c.1383C>G	p.Tyr461*	stop_gained	Exon 11 of 24	ENST00000456935.7	NP_000519.2
MAN2B1	NM_001440570.1 link	c.1386C>G	p.Tyr462*	stop_gained	Exon 11 of 24		NP_001427499.1
MAN2B1	NM_001173498.2 link	c.1380C>G	p.Tyr460*	stop_gained	Exon 11 of 24		NP_001166969.1
MAN2B1	XM_047438841.1 link	c.282C>G	p.Tyr94*	stop_gained	Exon 4 of 17		XP_047294797.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAN2B1	ENST00000456935.7 link	c.1383C>G	p.Tyr461*	stop_gained	Exon 11 of 24	1	NM_000528.4	ENSP00000395473.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.07e-7

AC:

AN:

1414556

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

699720

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32514

American (AMR)

AF:

0.0000264

AC:

AN:

37860

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25290

East Asian (EAS)

AF:

0.00

AC:

AN:

37222

South Asian (SAS)

AF:

0.00

AC:

AN:

80476

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49042

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5014

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1088638

Other (OTH)

AF:

0.00

AC:

AN:

58500

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Deficiency of alpha-mannosidase

Pathogenic:6

Oct 03, 2014

Baylor Genetics

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

Our laboratory reported dual molecular diagnoses in SCN8A (NM_014191.3, c.647T>G) and MAN2B1 (NM_000528.3, c.2782G>C and c.1383C>G in trans) in one individual with reported features that include delayed motor milestones, delayed speech, intellectual disability, hypotonia, seizure disorder (refractory epilepsy), abnormal movements (dyskinesia), minor dysmorphic features (flat nasal bridge, prominent eyes, full lips), microcephaly, dysphagia, and cortical visual impairment. The c.1383C>G variant in MAN2B1 has been previously reported as disease-causing [PMID 17979865].

Aug 04, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: The MAN2B1 c.1383C>G (p.Tyr461X) variant results in a premature termination codon, predicted to cause a truncated or absent MAN2B1 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. This variant was absent in 17720 control chromosomes, but has been observed in at least one alpha-mannosidosis patient in homozygous state. In addition, one clinical diagnostic laboratory classified this variant as likely pathogenic, and a similar variant, c.1383C>A (p.Y461X), was classified as pathogenic by Emory Genetics. c.1383C>A (p.Y461X) has been reported in multiple alpha-mannosidosis patients (PMID: 22161967). Taken together, this variant is classified as Pathogenic.

Feb 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Tyr461*) in the MAN2B1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MAN2B1 are known to be pathogenic (PMID: 9915946, 22161967). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with alpha-mannosidosis (PMID: 17979865). ClinVar contains an entry for this variant (Variation ID: 189068). For these reasons, this variant has been classified as Pathogenic.

May 25, 2021

Natera, Inc.

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

Nov 25, 2014

Counsyl

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

Sep 05, 2021

Genome-Nilou Lab

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Pathogenic:1

Sep 03, 2024

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 17979865, 27959697)

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.44

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.0

.;.

Eigen

Benign

-0.27

Eigen_PC

Benign

-0.66

FATHMM_MKL

Benign

0.36

LIST_S2

Benign

0.0

.;.

MetaRNN

Benign

0.0

.;.

MutationAssessor

Benign

0.0

.;.

PhyloP100

-0.93

PROVEAN

Benign

0.0

.;.

REVEL

Benign

0.0

Sift

Pathogenic

0.0

.;.

Sift4G

Pathogenic

0.0

.;.

Vest4

0.45

GERP RS

-5.9

Mutation Taster

=0/200

disease causing (ClinVar)

(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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over