rs141212446

Positions:

• chr19-12649920-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000528.4(MAN2B1):​c.2260G>A​(p.Glu754Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00173 in 1,613,084 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0018 (7 hom.)
• Consequence: MAN2B1 NM_000528.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:6
• Conservation: PhyloP100: 0.249

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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.024946094).
• BP6: Variant 19-12649920-C-T is Benign according to our data. Variant chr19-12649920-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 328262.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=3}. Variant chr19-12649920-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00129 (196/151972) while in subpopulation NFE AF= 0.00234 (159/67946). AF 95% confidence interval is 0.00204. There are 0 homozygotes in gnomad4. There are 91 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAN2B1	NM_000528.4	c.2260G>A	p.Glu754Lys	missense_variant	18/24	ENST00000456935.7
MAN2B1	NM_001173498.2	c.2257G>A	p.Glu753Lys	missense_variant	18/24
MAN2B1	XM_005259913.3	c.2263G>A	p.Glu755Lys	missense_variant	18/24
MAN2B1	XM_047438841.1	c.1159G>A	p.Glu387Lys	missense_variant	11/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAN2B1	ENST00000456935.7	c.2260G>A	p.Glu754Lys	missense_variant	18/24	1	NM_000528.4	A1
MAN2B1	ENST00000221363.8	c.2257G>A	p.Glu753Lys	missense_variant	18/24	1		P4
MAN2B1	ENST00000466794.5	n.2850G>A		non_coding_transcript_exon_variant	16/22	2

Frequencies

GnomAD3 genomes AF: 0.00129 AC: 196 AN: 151856 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000315

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000525

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00234

Gnomad OTH AF: 0.000482

GnomAD3 exomes AF: 0.00123 AC: 309 AN: 251484 Hom.: 2 AF XY: 0.00115 AC XY: 156 AN XY: 135914

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.000896

Gnomad ASJ exome AF: 0.00317

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000392

Gnomad FIN exome AF: 0.000231

Gnomad NFE exome AF: 0.00192

Gnomad OTH exome AF: 0.000814

GnomAD4 exome AF: 0.00177 AC: 2592 AN: 1461112 Hom.: 7 Cov.: 34 AF XY: 0.00175 AC XY: 1274 AN XY: 726876

Gnomad4 AFR exome AF: 0.000419

Gnomad4 AMR exome AF: 0.00105

Gnomad4 ASJ exome AF: 0.00222

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000255

Gnomad4 FIN exome AF: 0.000150

Gnomad4 NFE exome AF: 0.00212

Gnomad4 OTH exome AF: 0.00143

GnomAD4 genome AF: 0.00129 AC: 196 AN: 151972 Hom.: 0 Cov.: 30 AF XY: 0.00123 AC XY: 91 AN XY: 74272

Gnomad4 AFR AF: 0.000314

Gnomad4 AMR AF: 0.000524

Gnomad4 ASJ AF: 0.00346

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.00234

Gnomad4 OTH AF: 0.000477

Alfa AF: 0.00197 Hom.: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00140 AC: 12

ExAC AF: 0.00102 AC: 124

EpiCase AF: 0.00164

EpiControl AF: 0.00160

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Deficiency of alpha-mannosidase Uncertain:1 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
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. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 11, 2019	- -

not provided Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 16, 2023	BS1 -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	MAN2B1: BP4 -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 27, 2017	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Dec 07, 2023

Variant summary: MAN2B1 c.2260G>A (p.Glu754Lys) results in a conservative amino acid change located in the Glycosyl hydrolase family 38, C-terminal (IPR011682) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0012 in 251484 control chromosomes, predominantly at a frequency of 0.0019 within the Non-Finnish European subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.2 fold of the estimated maximal expected allele frequency for a pathogenic variant in MAN2B1 causing Alpha-Mannosidosis phenotype (0.0016), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, no occurrence of c.2260G>A in individuals affected with Alpha-Mannosidosis and no experimental evidence demonstrating its impact on protein function have been reported. Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as benign/likely benign (n=4) and VUS (n=3). Based on the evidence outlined above, the variant was classified as likely benign. -

MAN2B1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 11, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	15
DANN	Benign	0.33
DEOGEN2	Benign	0.17	T;.
Eigen	Benign	-0.97
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.72	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.025	T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	-0.39	N;.
MutationTaster	Benign	0.97	D;D
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.49	N;N
REVEL	Benign	0.20
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.020	B;.
Vest4		0.30
MVP		0.53
MPC		0.27
ClinPred		0.0013	T
GERP RS		-1.3
Varity_R		0.055
gMVP		0.57

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs141212446; hg19: chr19-12760734;