Genetic Variant MAGI2:p.Pro1431Leu (chr7-78019391-G-A) – 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_012301.4(MAGI2):c.4292C>T(p.Pro1431Leu) 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: 30)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

MAGI2
NM_012301.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.98

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:

Genome browser will be placed here

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
MAGI2	NM_012301.4 link	c.4292C>T	p.Pro1431Leu	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.4292C>T	p.Pro1431Leu	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:

1077232

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

513018

African (AFR)

AF:

0.00

AC:

AN:

22024

American (AMR)

AF:

0.00

AC:

AN:

8090

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

14226

East Asian (EAS)

AF:

0.00

AC:

AN:

24986

South Asian (SAS)

AF:

0.00

AC:

AN:

23892

European-Finnish (FIN)

AF:

0.00

AC:

AN:

20564

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2898

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

917980

Other (OTH)

AF:

0.00

AC:

AN:

42572

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Nephrotic syndrome 15

Uncertain:1

Apr 30, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.34

BayesDel_addAF

Benign

-0.085

BayesDel_noAF

Benign

-0.36

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.096

T;T;.;.

Eigen

Benign

0.024

Eigen_PC

Benign

0.088

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.91

D;D;D;D

M_CAP

Pathogenic

0.29

MetaRNN

Uncertain

0.45

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.81

.;L;.;.

PhyloP100

9.0

PrimateAI

Pathogenic

0.92

PROVEAN

Uncertain

-2.6

.;D;D;.

REVEL

Benign

0.23

Sift

Uncertain

0.0030

.;D;D;.

Sift4G

Uncertain

0.011

D;D;D;D

Polyphen

0.90, 0.94

.;P;P;.

Vest4

0.56, 0.42

MutPred

0.28

.;Gain of helix (P = 0.005);.;.;

MVP

0.068

MPC

1.1

ClinPred

0.91

GERP RS

3.2

Varity_R

0.13

gMVP

0.30

Mutation Taster

=70/30

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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