rs864621978

Variant names:

• chr19-12664823-T-A
• rs864621978
• NM_000528.4:c.599A>T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PM5 PP3_Strong PP5_Moderate

The NM_000528.4(MAN2B1):​c.599A>T​(p.His200Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H200N) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MAN2B1 NM_000528.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 5.83

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]

ENSG00000269590 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-12664824-G-T is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant 19-12664823-T-A is Pathogenic according to our data. Variant chr19-12664823-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 208256.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-12664823-T-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAN2B1	NM_000528.4	c.599A>T	p.His200Leu	missense_variant	Exon 4 of 24	ENST00000456935.7	NP_000519.2
MAN2B1	NM_001173498.2	c.599A>T	p.His200Leu	missense_variant	Exon 4 of 24		NP_001166969.1
MAN2B1	XM_005259913.3	c.599A>T	p.His200Leu	missense_variant	Exon 4 of 24		XP_005259970.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAN2B1	ENST00000456935.7	c.599A>T	p.His200Leu	missense_variant	Exon 4 of 24	1	NM_000528.4	ENSP00000395473.2
ENSG00000269590	ENST00000597961.1	c.*5A>T		downstream_gene_variant		4		ENSP00000472710.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Deficiency of alpha-mannosidase Pathogenic:1 Uncertain:1

Jun 07, 2012

ClinVar Staff, National Center for Biotechnology Information (NCBI)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mar 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces histidine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 200 of the MAN2B1 protein (p.His200Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with alpha mannosidosis (PMID: 15712269, 22161967, 26048034). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 208256). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MAN2B1 protein function. Experimental studies have shown that this missense change affects MAN2B1 function (PMID: 15712269). This variant disrupts the p.His200 amino acid residue in MAN2B1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16919251, 21505070, 22161967, 26048034). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	27
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.79	D;.
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Pathogenic	0.50	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Uncertain	0.45	D
MutationAssessor	Pathogenic	3.1	M;M
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-11	D;D
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.96
MutPred		0.94		Loss of disorder (P = 0.0397);Loss of disorder (P = 0.0397);
MVP		0.95
MPC		1.7
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.92
gMVP		0.97

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

Other links and lift over

dbSNP: rs864621978; hg19: chr19-12775637;