4-6575322-G-A

Position:

chr4-6575322-G-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM1PP5BS2

The NM_015274.3(MAN2B2):c.112G>A(p.Asp38Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000232 in 1,584,442 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00017 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00024 ( 2 hom. )

Consequence

MAN2B2
NM_015274.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2

Conservation

PhyloP100: 5.97

Variant links:

Genes affected

MAN2B2 (HGNC:29623): (mannosidase alpha class 2B member 2) Predicted to enable alpha-mannosidase activity. Predicted to be involved in mannose metabolic process. Located in extracellular exosome. [provided by Alliance of Genome Resources, Apr 2022]

MAN2B2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM1

In a binding_site (size 0) in uniprot entity MA2B2_HUMAN

PP5

Variant 4-6575322-G-A is Pathogenic according to our data. Variant chr4-6575322-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1065157.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAN2B2	NM_015274.3 linkuse as main transcript	c.112G>A	p.Asp38Asn	missense_variant	1/19	ENST00000285599.8
MAN2B2	NM_001292038.2 linkuse as main transcript	c.112G>A	p.Asp38Asn	missense_variant	1/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAN2B2	ENST00000285599.8 linkuse as main transcript	c.112G>A	p.Asp38Asn	missense_variant	1/19	1	NM_015274.3	P1	Q9Y2E5-1
MAN2B2	ENST00000504248.5 linkuse as main transcript	c.112G>A	p.Asp38Asn	missense_variant	1/19	2
MAN2B2	ENST00000505907.1 linkuse as main transcript	c.109G>A	p.Asp37Asn	missense_variant	1/17	2

Frequencies

GnomAD3 genomes

AF:

0.000171

AC:

AN:

152246

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000723

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000250

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000291

AC:

AN:

199310

Hom.:

AF XY:

0.000319

AC XY:

AN XY:

109630

show subpopulations

Gnomad AFR exome

AF:

0.0000848

Gnomad AMR exome

AF:

0.000328

Gnomad ASJ exome

AF:

0.000113

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000453

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000358

Gnomad OTH exome

AF:

0.000396

GnomAD4 exome

AF:

0.000238

AC:

341

AN:

1432078

Hom.:

Cov.:

AF XY:

0.000239

AC XY:

170

AN XY:

710966

show subpopulations

Gnomad4 AFR exome

AF:

0.000182

Gnomad4 AMR exome

AF:

0.000312

Gnomad4 ASJ exome

AF:

0.0000392

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000496

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000213

Gnomad4 OTH exome

AF:

0.000353

GnomAD4 genome

AF:

0.000171

AC:

AN:

152364

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74506

show subpopulations

Gnomad4 AFR

AF:

0.0000721

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000250

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000433

Hom.:

Bravo

AF:

0.000159

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000230

AC:

ESP6500EA

AF:

0.000234

AC:

ExAC

AF:

0.000250

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 25, 2024	- -
Uncertain significance, no assertion criteria provided	literature only	OMIM	Jul 16, 2020	- -

MAN2B2-related disorder

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Apr 09, 2021

Variant summary: MAN2B2 c.112G>A (p.Asp38Asn) results in a conservative amino acid change located in the Glycoside hydrosylase family 38, N-terminal domain (IPR000602) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00029 in 199310 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in MAN2B2 causing MAN2B2-Related Disorders, allowing no conclusion about variant significance. c.112G>A has been reported in the literature as a homozygous occurrence in at-least one individual affected with a MAN2B2-Related Disorder, specifically presenting as a congenital disorder of glycosylation (CDG). This individual was from a consanguineous family and the variant segregated with disease as obligate carrier parents and carrier siblings were unaffected (Verheijen_2020). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in a loss of cellular N-glycosylation in patient fibroblasts that was rescued upon induction of wild-type protein (Verheihen_2020). These findings were also supported by characteristic N-linked and free glycan profiles demonstrating an accumulation of Man2GlcNac2 glycans, consistent with defective glycoprotein degradation. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Pathogenic

0.27

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.65

D;.

Eigen

Uncertain

0.26

Eigen_PC

Benign

0.16

FATHMM_MKL

Uncertain

0.84

LIST_S2

Uncertain

0.95

D;D

M_CAP

Benign

0.069

MetaRNN

Uncertain

0.62

D;D

MetaSVM

Uncertain

-0.16

MutationAssessor

Pathogenic

4.1

H;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.85

PROVEAN

Uncertain

-3.7

D;D

REVEL

Pathogenic

0.82

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.83

MVP

0.83

MPC

0.56

ClinPred

0.95

GERP RS

1.9

Varity_R

0.94

gMVP

0.77

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over