rs1057516864

Variant names:

• chr19-12647460-C-CG
• rs1057516864
• NM_000528.4:c.2802dupC

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000528.4(MAN2B1):​c.2802dupC​(p.Val935ArgfsTer114) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: MAN2B1 NM_000528.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: -4.98

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 Pathogenic. Variant got 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 19-12647460-C-CG is Pathogenic according to our data. Variant chr19-12647460-C-CG is described in ClinVar as [Likely_pathogenic]. Clinvar id is 370914.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAN2B1	NM_000528.4	c.2802dupC	p.Val935ArgfsTer114	frameshift_variant	Exon 22 of 24	ENST00000456935.7	NP_000519.2
MAN2B1	NM_001173498.2	c.2799dupC	p.Val934ArgfsTer114	frameshift_variant	Exon 22 of 24		NP_001166969.1
MAN2B1	XM_005259913.3	c.2805dupC	p.Val936ArgfsTer114	frameshift_variant	Exon 22 of 24		XP_005259970.1
MAN2B1	XM_047438841.1	c.1701dupC	p.Val568ArgfsTer114	frameshift_variant	Exon 15 of 17		XP_047294797.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAN2B1	ENST00000456935.7	c.2802dupC	p.Val935ArgfsTer114	frameshift_variant	Exon 22 of 24	1	NM_000528.4	ENSP00000395473.2
ENSG00000269242	ENST00000597692.1	n.360dupC		non_coding_transcript_exon_variant	Exon 2 of 5	2		ENSP00000470240.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461886 Hom.: 0 Cov.: 34 AF XY: 0.00000275 AC XY: 2 AN XY: 727248

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: 0.0000116

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Deficiency of alpha-mannosidase Pathogenic:5

Jan 06, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant results in an extension of the MAN2B1 protein. Other variant(s) that result in a similarly extended protein product (p.Thr974Asnfs*) have been determined to be pathogenic (PMID: 22161967, 26048034). This suggests that these extensions are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 370914). This premature translational stop signal 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 creates a premature translational stop signal (p.Val935Argfs*) in the MAN2B1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 77 amino acid(s) of the MAN2B1 protein. -

Sep 05, 2021

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 12, 2016

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 12, 2022

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MAN2B1 c.2802dupC (p.Val935ArgfsX115+) causes a frameshift which results in an extension of the protein. The variant was absent in 251250 control chromosomes (gnomAD). c.2802dupC has been reported in the literature in at least one homozygous individual affected with Alpha-Mannosidosis (Riise Stensland_2012). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters have assessed the variant since 2014: one classified the variant as likely pathogenic and two as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

MAN2B1-related disorder Pathogenic:1

Aug 18, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The MAN2B1 c.2802dupC variant is predicted to result in a frameshift and premature protein termination (p.Val935Argfs*120). If translated, this variant is predicted to result in a MAN2B1 protein that is larger than the wild-type protein. It was reported in the homozygous state in an individual with alpha-mannosidosis, subtype 2 (Table S1 in Riise Stensland et al. 2012. PubMed ID: 22161967). Other frameshift variants expected to lead to extension beyond the canonical stop codon of the MAN2B1 gene have also been reported in patients with alpha-mannosidosis (e.g., Riise Stensland et al. 2012. PubMed ID: 22161967; patient 1 in Lehalle et al. 2019. PubMed ID: 31241255). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating is rare. Frameshift variants in MAN2B1 are expected to be pathogenic. Based on the collective evidence, this variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

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: rs1057516864; hg19: chr19-12758274;