rs864621975

Positions:

• chr19-12665801-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_000528.4(MAN2B1):​c.164G>T​(p.Cys55Phe) variant causes a missense change involving the alteration of a conserved nucleotide. 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MAN2B1 NM_000528.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2
• Conservation: PhyloP100: 7.54

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 Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.853
• PP5: Variant 19-12665801-C-A is Pathogenic according to our data. Variant chr19-12665801-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 208250.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}. Variant chr19-12665801-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAN2B1	NM_000528.4	c.164G>T	p.Cys55Phe	missense_variant	2/24	ENST00000456935.7	NP_000519.2
MAN2B1	NM_001173498.2	c.164G>T	p.Cys55Phe	missense_variant	2/24		NP_001166969.1
MAN2B1	XM_005259913.3	c.164G>T	p.Cys55Phe	missense_variant	2/24		XP_005259970.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAN2B1	ENST00000456935.7	c.164G>T	p.Cys55Phe	missense_variant	2/24	1	NM_000528.4	ENSP00000395473.2
ENSG00000269590	ENST00000597961.1	c.155G>T	p.Cys52Phe	missense_variant	3/5	4		ENSP00000472710.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1460508 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726660

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Deficiency of alpha-mannosidase Pathogenic:1 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 13, 2022	Experimental studies have shown that this missense change affects MAN2B1 function (PMID: 21505070, 22161967). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 208250). This missense change has been observed in individual(s) with alpha-mannosidosis (PMID: 22161967). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 55 of the MAN2B1 protein (p.Cys55Phe). -
Uncertain significance, no assertion criteria provided	literature only	ClinVar Staff, National Center for Biotechnology Information (NCBI)	Jun 07, 2012	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 27, 2022	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.70	D;.;.;.
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.77	T;T;T;T
M_CAP	Pathogenic	0.31	D
MetaRNN	Pathogenic	0.85	D;D;D;D
MetaSVM	Uncertain	0.36	D
MutationAssessor	Benign	1.9	L;L;.;.
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-7.7	D;D;.;.
REVEL	Pathogenic	0.84
Sift	Uncertain	0.0010	D;D;.;.
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		1.0	D;.;.;.
Vest4		0.94
MutPred		0.60		Loss of catalytic residue at T57 (P = 0.038);Loss of catalytic residue at T57 (P = 0.038);.;.;
MVP		0.99
MPC		1.9
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.89
gMVP		0.94

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

Other links and lift over

dbSNP: rs864621975; hg19: chr19-12776615;