rs80338679

chr19-12650103-C-T

Variant summary

Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PVS1 PM2 PP3_Strong PP5_Very_Strong

The NM_000528.4(MAN2B1):c.2165+1G>A variant causes a splice donor change. The variant allele was found at a frequency of 0.000000685 in 1,460,896 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/2 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MAN2B1 NM_000528.4 splice_donor
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2 O:1
• Conservation: PhyloP100: 7.10

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]

ACMG classification

Verdict is Pathogenic. Variant got 22 ACMG points.

• PVS1: Splicing variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 3.7, offset of -20, new splice context is: tcgGTgggg. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 19-12650103-C-T is Pathogenic according to our data. Variant chr19-12650103-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 21209.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAN2B1	NM_000528.4	c.2165+1G>A		splice_donor_variant		ENST00000456935.7
MAN2B1	NM_001173498.2	c.2162+1G>A		splice_donor_variant
MAN2B1	XM_005259913.3	c.2168+1G>A		splice_donor_variant
MAN2B1	XM_047438841.1	c.1064+1G>A		splice_donor_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAN2B1	ENST00000456935.7	c.2165+1G>A		splice_donor_variant		1	NM_000528.4	A1
MAN2B1	ENST00000221363.8	c.2162+1G>A		splice_donor_variant		1		P4
MAN2B1	ENST00000466794.5	n.2755+1G>A		splice_donor_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460896 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 726816

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: 0.0000166

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Deficiency of alpha-mannosidase Pathogenic:2 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jul 30, 2023	Studies have shown that disruption of this splice site is associated with altered splicing resulting in multiple RNA products (PMID: 9915946). ClinVar contains an entry for this variant (Variation ID: 21209). Disruption of this splice site has been observed in individuals with alpha-mannosidosis (PMID: 9915946). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 17 of the MAN2B1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MAN2B1 are known to be pathogenic (PMID: 9915946, 22161967). This variant disrupts a region of the MAN2B1 protein in which other variant(s) (p.Trp714Arg) have been determined to be pathogenic (PMID: 9915946, 22161967). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.19
Cadd	Pathogenic	34
Dann	Uncertain	0.99
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Uncertain	0.90	D
MutationTaster	Benign	1.0	A;A
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.91
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.43		Position offset: 25
DS_DL_spliceai		0.99		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs80338679; hg19: chr19-12760917;