19-12646685-TG-T

Position:

• chr19-12646685-TG-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_000528.4(MAN2B1):​c.2970del​(p.Thr991ArgfsTer42) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. I990I) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: MAN2B1 NM_000528.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.90

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 Likely_pathogenic. Variant got 6 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0217 CDS is truncated, and there are 3 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-12646685-TG-T is Pathogenic according to our data. Variant chr19-12646685-TG-T is described in ClinVar as [Pathogenic]. Clinvar id is 2413176.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAN2B1	NM_000528.4	c.2970del	p.Thr991ArgfsTer42	frameshift_variant	24/24	ENST00000456935.7
MAN2B1	NM_001173498.2	c.2967del	p.Thr990ArgfsTer42	frameshift_variant	24/24
MAN2B1	XM_005259913.3	c.2973del	p.Thr992ArgfsTer42	frameshift_variant	24/24
MAN2B1	XM_047438841.1	c.1869del	p.Thr624ArgfsTer42	frameshift_variant	17/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAN2B1	ENST00000456935.7	c.2970del	p.Thr991ArgfsTer42	frameshift_variant	24/24	1	NM_000528.4	A1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Deficiency of alpha-mannosidase Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Suma Genomics, Suma Genomics

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Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.24		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.24		Position offset: 47

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-12757499;