Genetic Variant MAN2A2:p.Asn81Lys (chr15-90905361-C-A) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_006122.4(MAN2A2):c.243C>A(p.Asn81Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000988 in 1,613,828 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00072 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0010 ( 1 hom. )

Consequence

MAN2A2
NM_006122.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.390

Variant links:

Genes affected

MAN2A2 (HGNC:6825): (mannosidase alpha class 2A member 2) Predicted to enable alpha-mannosidase activity. Predicted to be involved in N-glycan processing and protein deglycosylation. Predicted to be integral component of membrane. Predicted to be active in Golgi membrane. [provided by Alliance of Genome Resources, Apr 2022]

MAN2A2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.014657855).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAN2A2	NM_006122.4 link	c.243C>A	p.Asn81Lys	missense_variant	Exon 3 of 23	ENST00000559717.6	NP_006113.2	P49641-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAN2A2	ENST00000559717.6 link	c.243C>A	p.Asn81Lys	missense_variant	Exon 3 of 23	2	NM_006122.4	ENSP00000452948.1		P49641-3

Frequencies

GnomAD3 genomes

AF:

0.000716

AC:

109

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000916

Gnomad ASJ

AF:

0.000864

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00116

Gnomad OTH

AF:

0.00192

GnomAD3 exomes

AF:

0.000836

AC:

210

AN:

251128

Hom.:

AF XY:

0.000810

AC XY:

110

AN XY:

135834

show subpopulations

Gnomad AFR exome

AF:

0.000247

Gnomad AMR exome

AF:

0.00127

Gnomad ASJ exome

AF:

0.000596

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000261

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00120

Gnomad OTH exome

AF:

0.00196

GnomAD4 exome

AF:

0.00102

AC:

1486

AN:

1461512

Hom.:

Cov.:

AF XY:

0.000997

AC XY:

725

AN XY:

727072

show subpopulations

Gnomad4 AFR exome

AF:

0.000179

Gnomad4 AMR exome

AF:

0.00132

Gnomad4 ASJ exome

AF:

0.000344

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000220

Gnomad4 FIN exome

AF:

0.000113

Gnomad4 NFE exome

AF:

0.00120

Gnomad4 OTH exome

AF:

0.000828

GnomAD4 genome

AF:

0.000716

AC:

109

AN:

152316

Hom.:

Cov.:

AF XY:

0.000644

AC XY:

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.000192

Gnomad4 AMR

AF:

0.000914

Gnomad4 ASJ

AF:

0.000864

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00116

Gnomad4 OTH

AF:

0.00190

Alfa

AF:

0.00108

Hom.:

Bravo

AF:

0.000933

TwinsUK

AF:

0.00189

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00128

AC:

ExAC

AF:

0.000799

AC:

EpiCase

AF:

0.000872

EpiControl

AF:

0.00130

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 14, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.243C>A (p.N81K) alteration is located in exon 2 (coding exon 2) of the MAN2A2 gene. This alteration results from a C to A substitution at nucleotide position 243, causing the asparagine (N) at amino acid position 81 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.47

CADD

Benign

0.17

DANN

Benign

0.88

DEOGEN2

Benign

0.076

.;T;T

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.21

LIST_S2

Uncertain

0.87

D;.;D

M_CAP

Uncertain

0.089

MetaRNN

Benign

0.015

T;T;T

MetaSVM

Benign

-0.71

MutationAssessor

Benign

1.5

.;L;L

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-2.0

N;.;N

REVEL

Benign

0.23

Sift

Benign

0.049

D;.;T

Sift4G

Benign

0.14

T;T;T

Polyphen

0.41

.;B;B

Vest4

0.33, 0.33

MutPred

0.35

Gain of ubiquitination at N81 (P = 0.0094);Gain of ubiquitination at N81 (P = 0.0094);Gain of ubiquitination at N81 (P = 0.0094);

MVP

0.53

MPC

0.49

ClinPred

0.026

GERP RS

-8.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.058

gMVP

0.20

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