Genetic Variant NM_012301.4:c.4259G>T (chr7-78019424-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.4259G>T(p.Gly1420Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000464 in 1,077,210 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. G1420E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000014 ( 0 hom., cov: 30)

Exomes 𝑓: 0.0000032 ( 0 hom. )

Consequence

MAGI2
NM_012301.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.04

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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.18421394).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAGI2	NM_012301.4 link	c.4259G>T	p.Gly1420Val	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.4259G>T	p.Gly1420Val	missense_variant	Exon 22 of 22	1	NM_012301.4	ENSP00000346151.4		Q86UL8-1

Frequencies

GnomAD3 genomes

AF:

0.0000137

AC:

AN:

145726

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:

0.000201

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000152

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000322

AC:

AN:

931484

Hom.:

Cov.:

AF XY:

0.00000229

AC XY:

AN XY:

436496

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

18318

American (AMR)

AF:

0.00

AC:

AN:

3704

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

8414

East Asian (EAS)

AF:

0.0000744

AC:

AN:

13444

South Asian (SAS)

AF:

0.0000555

AC:

AN:

18022

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8918

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2106

European-Non Finnish (NFE)

AF:

0.00000121

AC:

AN:

825106

Other (OTH)

AF:

0.00

AC:

AN:

33452

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000137

AC:

AN:

145726

Hom.:

Cov.:

AF XY:

0.0000282

AC XY:

AN XY:

70840

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

40672

American (AMR)

AF:

0.00

AC:

AN:

14744

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3396

East Asian (EAS)

AF:

0.000201

AC:

AN:

4978

South Asian (SAS)

AF:

0.00

AC:

AN:

4788

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8300

Middle Eastern (MID)

AF:

0.00

AC:

AN:

306

European-Non Finnish (NFE)

AF:

0.0000152

AC:

AN:

65628

Other (OTH)

AF:

0.00

AC:

AN:

2012

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.54

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.079

T;T;.;.

Eigen

Benign

-0.17

Eigen_PC

Benign

-0.24

FATHMM_MKL

Benign

0.22

LIST_S2

Benign

0.65

T;T;T;T

M_CAP

Uncertain

0.25

MetaRNN

Benign

0.18

T;T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.34

.;N;.;.

PhyloP100

1.0

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

-1.0

.;N;N;.

REVEL

Benign

0.073

Sift

Uncertain

0.0060

.;D;D;.

Sift4G

Benign

0.12

T;T;T;T

Polyphen

0.99, 1.0

.;D;D;.

Vest4

0.25, 0.32

MutPred

0.20

.;Loss of relative solvent accessibility (P = 0.0186);.;.;

MVP

0.10

MPC

1.4

ClinPred

0.69

GERP RS

1.9

Varity_R

0.12

gMVP

0.16

Mutation Taster

=92/8

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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NM_012301.4:c.4259G>T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over