19-12646515-G-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_000528.4(MAN2B1):c.*105C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000999 in 871,058 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00081 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0010 (4 hom.)
• Consequence: MAN2B1 NM_000528.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.788

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_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAN2B1	NM_000528.4	c.*105C>G		3_prime_UTR_variant	24/24	ENST00000456935.7
MAN2B1	NM_001173498.2	c.*105C>G		3_prime_UTR_variant	24/24
MAN2B1	XM_005259913.3	c.*105C>G		3_prime_UTR_variant	24/24
MAN2B1	XM_047438841.1	c.*105C>G		3_prime_UTR_variant	17/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAN2B1	ENST00000456935.7	c.*105C>G		3_prime_UTR_variant	24/24	1	NM_000528.4	A1

Frequencies

GnomAD3 genomes AF: 0.000815 AC: 124 AN: 152140 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.00565

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000764

Gnomad OTH AF: 0.000478

GnomAD4 exome AF: 0.00104 AC: 747 AN: 718800 Hom.: 4 Cov.: 9 AF XY: 0.00101 AC XY: 384 AN XY: 380434

Gnomad4 AFR exome AF: 0.000105

Gnomad4 AMR exome AF: 0.000136

Gnomad4 ASJ exome AF: 0.000143

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00103

Gnomad4 FIN exome AF: 0.00478

Gnomad4 NFE exome AF: 0.000889

Gnomad4 OTH exome AF: 0.000808

GnomAD4 genome AF: 0.000808 AC: 123 AN: 152258 Hom.: 0 Cov.: 31 AF XY: 0.000967 AC XY: 72 AN XY: 74462

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.00565

Gnomad4 NFE AF: 0.000764

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000424 Hom.: 0

Bravo AF: 0.000506

Asia WGS AF: 0.000866 AC: 4 AN: 3478

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

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
Cadd	Benign	1.0
Dann	Benign	0.58

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs547349667; hg19: chr19-12757329;