Genetic Variant MAN2A2:p.Arg44Gly (chr15-90904337-C-G) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_006122.4(MAN2A2):c.130C>G(p.Arg44Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000415 in 1,613,118 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000043 ( 0 hom. )

Consequence

MAN2A2
NM_006122.4 missense, splice_region

Scores

Splicing: ADA: 0.06066

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.51

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.38034227).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAN2A2	NM_006122.4 link	c.130C>G	p.Arg44Gly	missense_variant, splice_region_variant	Exon 2 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.130C>G	p.Arg44Gly	missense_variant, splice_region_variant	Exon 2 of 23	2	NM_006122.4	ENSP00000452948.1		P49641-3

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000319

AC:

AN:

250534

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

135454

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000620

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000431

AC:

AN:

1460978

Hom.:

Cov.:

AF XY:

0.0000413

AC XY:

AN XY:

726650

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000549

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152140

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74320

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000340

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 14, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.130C>G (p.R44G) alteration is located in exon 1 (coding exon 1) of the MAN2A2 gene. This alteration results from a C to G substitution at nucleotide position 130, causing the arginine (R) at amino acid position 44 to be replaced by a glycine (G). 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

0.31

BayesDel_addAF

Benign

-0.077

BayesDel_noAF

Benign

-0.18

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.066

T;.;.;T;T;T

Eigen

Uncertain

0.19

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.92

D;D;D;.;D;D

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.38

T;T;T;T;T;T

MetaSVM

Benign

-0.47

MutationAssessor

Uncertain

2.0

.;.;.;M;.;M

PrimateAI

Uncertain

0.77

PROVEAN

Uncertain

-3.6

D;D;D;.;D;N

REVEL

Uncertain

0.42

Sift

Benign

0.080

T;T;T;.;T;T

Sift4G

Uncertain

0.031

D;D;D;T;D;T

Polyphen

0.80

.;.;.;P;.;P

Vest4

0.58

MutPred

0.34

Loss of catalytic residue at R44 (P = 0.05);Loss of catalytic residue at R44 (P = 0.05);Loss of catalytic residue at R44 (P = 0.05);Loss of catalytic residue at R44 (P = 0.05);Loss of catalytic residue at R44 (P = 0.05);Loss of catalytic residue at R44 (P = 0.05);

MVP

0.82

MPC

0.91

ClinPred

0.77

GERP RS

3.6

Varity_R

0.45

gMVP

0.52

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.061

dbscSNV1_RF

Benign

0.33

SpliceAI score (max)

0.030

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