19-12649169-GC-GCC

Position:

• chr19-12649169-GC-GCC

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.2402dupG​(p.Ser802fs) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000806 in 1,612,488 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: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: MAN2B1 NM_000528.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 4.59

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 (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 19-12649169-G-GC is Pathogenic according to our data. Variant chr19-12649169-G-GC is described in ClinVar as [Likely_pathogenic]. Clinvar id is 195465.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAN2B1	NM_000528.4	c.2402dupG	p.Ser802fs	frameshift_variant	20/24	ENST00000456935.7	NP_000519.2
MAN2B1	NM_001173498.2	c.2399dupG	p.Ser801fs	frameshift_variant	20/24		NP_001166969.1
MAN2B1	XM_005259913.3	c.2405dupG	p.Ser803fs	frameshift_variant	20/24		XP_005259970.1
MAN2B1	XM_047438841.1	c.1301dupG	p.Ser435fs	frameshift_variant	13/17		XP_047294797.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAN2B1	ENST00000456935.7	c.2402dupG	p.Ser802fs	frameshift_variant	20/24	1	NM_000528.4	ENSP00000395473.2
MAN2B1	ENST00000221363.8	c.2399dupG	p.Ser801fs	frameshift_variant	20/24	1		ENSP00000221363.4
MAN2B1	ENST00000466794.5	n.2992dupG		non_coding_transcript_exon_variant	18/22	2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152120 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000822 AC: 12 AN: 1460368 Hom.: 0 Cov.: 33 AF XY: 0.0000110 AC XY: 8 AN XY: 726488

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: 0.0000108

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152120 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74314

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Deficiency of alpha-mannosidase Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 26, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	Jul 29, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	May 08, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Apr 03, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 04, 2023	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 195465). This premature translational stop signal has been observed in individuals with clinical features of alpha-mannosidosis (PMID: 22161967, 26048034, 26633546). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ser802Glnfs*129) 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). -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 31, 2021	- -
Pathogenic, no assertion criteria provided	research	Biochemistry And Molecular Medicine, Center For Genetics And Inherited Diseases, Taibah University	Apr 25, 2024	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jun 01, 2015

- -

Computational scores

Source: dbNSFP v4.3

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: rs797044680; hg19: chr19-12759983;