19-12646578-C-T

Position:

• chr19-12646578-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000528.4(MAN2B1):​c.*42G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00878 in 1,460,686 control chromosomes in the GnomAD database, including 67 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0064 (2 hom., cov: 31)
  • Exomes 𝑓: 0.0091 (65 hom.)
• Consequence: MAN2B1 NM_000528.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.08

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]

ENSG00000269242 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 19-12646578-C-T is Benign according to our data. Variant chr19-12646578-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 328250.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00641 (977/152302) while in subpopulation NFE AF= 0.0093 (633/68028). AF 95% confidence interval is 0.0087. There are 2 homozygotes in gnomad4. There are 470 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAN2B1	NM_000528.4	c.*42G>A		3_prime_UTR_variant	24/24	ENST00000456935.7	NP_000519.2
MAN2B1	NM_001173498.2	c.*42G>A		3_prime_UTR_variant	24/24		NP_001166969.1
MAN2B1	XM_005259913.3	c.*42G>A		3_prime_UTR_variant	24/24		XP_005259970.1
MAN2B1	XM_047438841.1	c.*42G>A		3_prime_UTR_variant	17/17		XP_047294797.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAN2B1	ENST00000456935	c.*42G>A		3_prime_UTR_variant	24/24	1	NM_000528.4	ENSP00000395473.2
ENSG00000269242	ENST00000597692.1	n.*42G>A		non_coding_transcript_exon_variant	4/5	2		ENSP00000470240.1
ENSG00000269242	ENST00000597692.1	n.*42G>A		3_prime_UTR_variant	4/5	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

GnomAD3 exomes AF: 0.00645 AC: 1606 AN: 248996 Hom.: 4 AF XY: 0.00617 AC XY: 831 AN XY: 134684

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 SAS exome AF: 0.00105

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

Gnomad4 AFR exome AF: 0.00192

Gnomad4 AMR exome AF: 0.00390

Gnomad4 ASJ exome AF: 0.0100

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00117

Gnomad4 FIN exome AF: 0.0114

Gnomad4 NFE exome AF: 0.0104

Gnomad4 OTH exome AF: 0.00861

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

Gnomad4 AFR AF: 0.00200

Gnomad4 AMR AF: 0.00589

Gnomad4 ASJ AF: 0.00836

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000828

Gnomad4 FIN AF: 0.0120

Gnomad4 NFE AF: 0.00930

Gnomad4 OTH AF: 0.00474

Alfa AF: 0.00733 Hom.: 0

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

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2023	MAN2B1: BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 26, 2021	See Variant Classification Assertion Criteria. -

Deficiency of alpha-mannosidase Benign:1

Likely benign, 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 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
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

Publications

LitVar

Other links and lift over

dbSNP: rs149101136; hg19: chr19-12757392;