19-12647271-C-G

Position:

• chr19-12647271-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_000528.4(MAN2B1):​c.2885G>C​(p.Arg962Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,860 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MAN2B1 NM_000528.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.110

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]

ENSG00000269242 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a chain Lysosomal alpha-mannosidase E peptide (size 128) in uniprot entity MA2B1_HUMAN there are 7 pathogenic changes around while only 1 benign (88%) in NM_000528.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.916

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAN2B1	NM_000528.4	c.2885G>C	p.Arg962Pro	missense_variant	23/24	ENST00000456935.7	NP_000519.2
MAN2B1	NM_001173498.2	c.2882G>C	p.Arg961Pro	missense_variant	23/24		NP_001166969.1
MAN2B1	XM_005259913.3	c.2888G>C	p.Arg963Pro	missense_variant	23/24		XP_005259970.1
MAN2B1	XM_047438841.1	c.1784G>C	p.Arg595Pro	missense_variant	16/17		XP_047294797.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAN2B1	ENST00000456935.7	c.2885G>C	p.Arg962Pro	missense_variant	23/24	1	NM_000528.4	ENSP00000395473.2
ENSG00000269242	ENST00000597692.1	n.443G>C		non_coding_transcript_exon_variant	3/5	2		ENSP00000470240.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251458 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135914

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461860 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727236

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Deficiency of alpha-mannosidase Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 10, 2022

This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 962 of the MAN2B1 protein (p.Arg962Pro). 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 are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with MAN2B1-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.003%). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.029	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	15
DANN	Benign	0.93
DEOGEN2	Uncertain	0.55	D;.
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.071	N
LIST_S2	Benign	0.77	T;T
M_CAP	Benign	0.045	D
MetaRNN	Pathogenic	0.92	D;D
MetaSVM	Benign	-0.58	T
MutationAssessor	Uncertain	2.6	M;.
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-3.2	D;D
REVEL	Uncertain	0.34
Sift	Benign	0.20	T;T
Sift4G	Benign	0.22	T;T
Polyphen		0.89	P;.
Vest4		0.63
MutPred		0.72		Loss of MoRF binding (P = 0.0031);.;
MVP		0.82
MPC		0.86
ClinPred		0.90	D
GERP RS		-4.2
Varity_R		0.83
gMVP		0.83

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: rs750173812; hg19: chr19-12758085;