19-12646578-C-T

Variant names:

• chr19-12646578-C-T
• rs149101136
• ENST00000597692.1:n.*42G>A

Variant summary

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

The ENST00000597692.1(ENSG00000269242):​n.*42G>A 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 0.00878 in 1,460,686 control chromosomes in the GnomAD database, including 67 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0064 (2 hom., cov: 31)
  • Exomes 𝑓: 0.0091 (65 hom.)
• Consequence: ENSG00000269242 ENST00000597692.1 non_coding_transcript_exon
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.08
• Publications: 2 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 GnomAd4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAN2B1	NM_000528.4	c.*42G>A		3_prime_UTR_variant	Exon 24 of 24	ENST00000456935.7	NP_000519.2
MAN2B1	NM_001440570.1	c.*42G>A		3_prime_UTR_variant	Exon 24 of 24		NP_001427499.1
MAN2B1	NM_001173498.2	c.*42G>A		3_prime_UTR_variant	Exon 24 of 24		NP_001166969.1
MAN2B1	XM_047438841.1	c.*42G>A		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.*42G>A		non_coding_transcript_exon_variant	Exon 4 of 5	2		ENSP00000470240.1
MAN2B1	ENST00000456935.7	c.*42G>A		3_prime_UTR_variant	Exon 24 of 24	1	NM_000528.4	ENSP00000395473.2
ENSG00000269242	ENST00000597692.1	n.*42G>A		3_prime_UTR_variant	Exon 4 of 5	2		ENSP00000470240.1

Frequencies

GnomAD3 genomes AF: 0.00643 AC: 978 AN: 152184 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.00200

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00589

Gnomad ASJ AF: 0.00836

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.0120

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00932

Gnomad OTH AF: 0.00479

GnomAD2 exomes AF: 0.00645 AC: 1606 AN: 248996 AF XY: 0.00617

Gnomad AFR exome AF: 0.00199

Gnomad AMR exome AF: 0.00408

Gnomad ASJ exome AF: 0.0107

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0106

Gnomad NFE exome AF: 0.00907

Gnomad OTH exome AF: 0.00789

GnomAD4 exome AF: 0.00906 AC: 11849 AN: 1308384 Hom.: 65 Cov.: 21 AF XY: 0.00876 AC XY: 5773 AN XY: 658788

African (AFR) AF: 0.00192 AC: 58 AN: 30224

American (AMR) AF: 0.00390 AC: 173 AN: 44346

Ashkenazi Jewish (ASJ) AF: 0.0100 AC: 253 AN: 25226

East Asian (EAS) AF: 0.00 AC: 0 AN: 38936

South Asian (SAS) AF: 0.00117 AC: 97 AN: 83050

European-Finnish (FIN) AF: 0.0114 AC: 606 AN: 53290

Middle Eastern (MID) AF: 0.00436 AC: 24 AN: 5506

European-Non Finnish (NFE) AF: 0.0104 AC: 10161 AN: 972382

Other (OTH) AF: 0.00861 AC: 477 AN: 55424

GnomAD4 genome AF: 0.00641 AC: 977 AN: 152302 Hom.: 2 Cov.: 31 AF XY: 0.00631 AC XY: 470 AN XY: 74468

African (AFR) AF: 0.00200 AC: 83 AN: 41558

American (AMR) AF: 0.00589 AC: 90 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00836 AC: 29 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000828 AC: 4 AN: 4832

European-Finnish (FIN) AF: 0.0120 AC: 127 AN: 10618

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

European-Non Finnish (NFE) AF: 0.00930 AC: 633 AN: 68028

Other (OTH) AF: 0.00474 AC: 10 AN: 2110

Alfa AF: 0.00736 Hom.: 1

Bravo AF: 0.00605

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

May 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MAN2B1: BS2 -

May 26, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

See Variant Classification Assertion Criteria. -

Deficiency of alpha-mannosidase Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.32
DANN	Benign	0.40
PhyloP100		-1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs149101136; hg19: chr19-12757392;