Genetic Variant MAGI2:p.Val1429Phe (chr7-78019398-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_012301.4(MAGI2):c.4285G>T(p.Val1429Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1429I) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

MAGI2
NM_012301.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.39

Publications

0 publications found

Variant links:

Genes affected

MAGI2 (HGNC:18957): (membrane associated guanylate kinase, WW and PDZ domain containing 2) The protein encoded by this gene interacts with atrophin-1. Atrophin-1 contains a polyglutamine repeat, expansion of which is responsible for dentatorubral and pallidoluysian atrophy. This encoded protein is characterized by two WW domains, a guanylate kinase-like domain, and multiple PDZ domains. It has structural similarity to the membrane-associated guanylate kinase homologue (MAGUK) family. [provided by RefSeq, Jul 2008]

MAGI2 Gene-Disease associations (from GenCC):

nephrotic syndrome 15
Inheritance: AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
familial idiopathic steroid-resistant nephrotic syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
genetic developmental and epileptic encephalopathy
Inheritance: AD Classification: LIMITED Submitted by: G2P
epilepsy
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

MAGI2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.1986708).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAGI2	NM_012301.4 link	c.4285G>T	p.Val1429Phe	missense_variant	Exon 22 of 22	ENST00000354212.9	NP_036433.2	Q86UL8-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAGI2	ENST00000354212.9 link	c.4285G>T	p.Val1429Phe	missense_variant	Exon 22 of 22	1	NM_012301.4	ENSP00000346151.4		Q86UL8-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1058920

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

503146

African (AFR)

AF:

0.00

AC:

AN:

21648

American (AMR)

AF:

0.00

AC:

AN:

7636

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

13378

East Asian (EAS)

AF:

0.00

AC:

AN:

24164

South Asian (SAS)

AF:

0.00

AC:

AN:

22234

European-Finnish (FIN)

AF:

0.00

AC:

AN:

19294

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2778

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

906302

Other (OTH)

AF:

0.00

AC:

AN:

41486

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.54

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.069

T;T;.;.

Eigen

Benign

-0.75

Eigen_PC

Benign

-0.69

FATHMM_MKL

Benign

0.49

LIST_S2

Uncertain

0.87

D;D;D;D

M_CAP

Uncertain

0.26

MetaRNN

Benign

0.20

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.81

.;L;.;.

PhyloP100

2.4

PrimateAI

Pathogenic

0.91

PROVEAN

Benign

-0.90

.;N;N;.

REVEL

Benign

0.070

Sift

Uncertain

0.012

.;D;D;.

Sift4G

Benign

0.064

T;T;T;T

Polyphen

0.096, 0.15

.;B;B;.

Vest4

0.60, 0.38

MutPred

0.27

.;Loss of MoRF binding (P = 0.082);.;.;

MVP

0.16

MPC

1.4

ClinPred

0.68

GERP RS

0.50

Varity_R

0.086

gMVP

0.42

Mutation Taster

=87/13

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

Computational scores

Splicing

Publications

Other links and lift over