19-12646529-G-A

Variant names:

• chr19-12646529-G-A
• rs145108101
• ENST00000597692.1:n.*91C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The ENST00000597692.1(ENSG00000269242):​n.*91C>T variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000596 in 1,007,482 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00066 (2 hom.)
• Consequence: ENSG00000269242 ENST00000597692.1 non_coding_transcript_exon
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.453
• Publications: 0 publications found

Genes affected

ENSG00000269242 (HGNC:):

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 Gene-Disease associations (from GenCC):

• alpha-mannosidosis

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Genomics England PanelApp, Myriad Women’s Health, G2P, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BS2: High Homozygotes in GnomAdExome4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAN2B1	NM_000528.4	c.*91C>T		3_prime_UTR_variant	Exon 24 of 24	ENST00000456935.7	NP_000519.2
MAN2B1	NM_001440570.1	c.*91C>T		3_prime_UTR_variant	Exon 24 of 24		NP_001427499.1
MAN2B1	NM_001173498.2	c.*91C>T		3_prime_UTR_variant	Exon 24 of 24		NP_001166969.1
MAN2B1	XM_047438841.1	c.*91C>T		3_prime_UTR_variant	Exon 17 of 17		XP_047294797.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENSG00000269242	ENST00000597692.1	n.*91C>T		non_coding_transcript_exon_variant	Exon 4 of 5	2		ENSP00000470240.1
MAN2B1	ENST00000456935.7	c.*91C>T		3_prime_UTR_variant	Exon 24 of 24	1	NM_000528.4	ENSP00000395473.2
ENSG00000269242	ENST00000597692.1	n.*91C>T		3_prime_UTR_variant	Exon 4 of 5	2		ENSP00000470240.1

Frequencies

GnomAD3 genomes AF: 0.000243 AC: 37 AN: 152124 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00482

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000478

GnomAD4 exome AF: 0.000658 AC: 563 AN: 855240 Hom.: 2 Cov.: 12 AF XY: 0.000616 AC XY: 275 AN XY: 446492

African (AFR) AF: 0.0000461 AC: 1 AN: 21670

American (AMR) AF: 0.000128 AC: 5 AN: 38956

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21946

East Asian (EAS) AF: 0.0145 AC: 526 AN: 36242

South Asian (SAS) AF: 0.0000553 AC: 4 AN: 72332

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51574

Middle Eastern (MID) AF: 0.000214 AC: 1 AN: 4668

European-Non Finnish (NFE) AF: 0.0000370 AC: 21 AN: 567400

Other (OTH) AF: 0.000124 AC: 5 AN: 40452

GnomAD4 genome AF: 0.000243 AC: 37 AN: 152242 Hom.: 0 Cov.: 31 AF XY: 0.000242 AC XY: 18 AN XY: 74434

African (AFR) AF: 0.0000963 AC: 4 AN: 41530

American (AMR) AF: 0.000262 AC: 4 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00483 AC: 25 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68024

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.0000693 Hom.: 0

Bravo AF: 0.000181

Asia WGS AF: 0.00346 AC: 12 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Deficiency of alpha-mannosidase Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	-0.88
CADD	Benign	7.4
DANN	Benign	0.74
PhyloP100		0.45
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs145108101; hg19: chr19-12757343;