Genetic Variant MDGA2:p.Glu266Lys (chr14-47131843-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001113498.3(MDGA2):c.796G>A(p.Glu266Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

MDGA2
NM_001113498.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.57

Publications

0 publications found

Variant links:

Genes affected

MDGA2 (HGNC:19835): (MAM domain containing glycosylphosphatidylinositol anchor 2) Predicted to be involved in regulation of presynapse assembly; regulation of synaptic membrane adhesion; and spinal cord motor neuron differentiation. Predicted to act upstream of or within neuron migration and pattern specification process. Predicted to be located in extracellular region and plasma membrane. Predicted to be active in GABA-ergic synapse and glutamatergic synapse. [provided by Alliance of Genome Resources, Apr 2022]

MDGA2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MDGA2	NM_001113498.3 link	c.796G>A	p.Glu266Lys	missense_variant	Exon 5 of 17	ENST00000399232.8	NP_001106970.4	Q7Z553-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MDGA2	ENST00000399232.8 link	c.796G>A	p.Glu266Lys	missense_variant	Exon 5 of 17	1	NM_001113498.3	ENSP00000382178.4		Q7Z553-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1418282

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

701922

African (AFR)

AF:

0.00

AC:

AN:

32854

American (AMR)

AF:

0.00

AC:

AN:

43260

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24842

East Asian (EAS)

AF:

0.00

AC:

AN:

38996

South Asian (SAS)

AF:

0.00

AC:

AN:

80904

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51808

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5614

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1081802

Other (OTH)

AF:

0.00

AC:

AN:

58202

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 18, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.589G>A (p.V197I) alteration is located in exon 3 (coding exon 3) of the MDGA2 gene. This alteration results from a G to A substitution at nucleotide position 589, causing the valine (V) at amino acid position 197 to be replaced by an isoleucine (I). 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

Pathogenic

0.87

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Uncertain

0.070

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.027

.;T

Eigen

Pathogenic

0.71

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.97

D;D

M_CAP

Benign

0.0036

MetaRNN

Uncertain

0.58

D;D

MetaSVM

Benign

-0.79

MutationAssessor

Benign

1.0

.;L

PhyloP100

7.6

PrimateAI

Pathogenic

0.91

PROVEAN

Benign

-1.8

N;.

REVEL

Benign

0.21

Sift

Benign

0.074

T;.

Polyphen

1.0

.;D

MutPred

0.55

.;Gain of catalytic residue at F193 (P = 0.0018);

MVP

0.16

ClinPred

0.97

GERP RS

5.4

PromoterAI

-0.030

Neutral

(source)

Varity_R

0.25

gMVP

0.65

Mutation Taster

=69/31

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over