Genetic Variant MAGI2:p.Pro1419Thr (chr7-78019428-G-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_012301.4(MAGI2):c.4255C>A(p.Pro1419Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000011 in 905,110 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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. P1419A) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 30)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

MAGI2
NM_012301.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.13

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: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.10871175).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAGI2	NM_012301.4 link	c.4255C>A	p.Pro1419Thr	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.4255C>A	p.Pro1419Thr	missense_variant	Exon 22 of 22	1	NM_012301.4	ENSP00000346151.4		Q86UL8-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.0000110

AC:

AN:

905110

Hom.:

Cov.:

AF XY:

0.00000946

AC XY:

AN XY:

422888

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

17612

American (AMR)

AF:

0.00

AC:

AN:

3042

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

7450

East Asian (EAS)

AF:

0.00

AC:

AN:

10680

South Asian (SAS)

AF:

0.00

AC:

AN:

17758

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6670

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1994

European-Non Finnish (NFE)

AF:

0.0000124

AC:

AN:

808226

Other (OTH)

AF:

0.00

AC:

AN:

31678

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.66

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.055

T;T;.;.

Eigen

Benign

-0.89

Eigen_PC

Benign

-0.84

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.53

T;T;T;T

M_CAP

Uncertain

0.23

MetaRNN

Benign

0.11

T;T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.34

.;N;.;.

PhyloP100

1.1

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

-0.21

.;N;N;.

REVEL

Benign

0.087

Sift

Benign

0.12

.;T;T;.

Sift4G

Benign

0.44

T;T;T;T

Polyphen

0.0

.;B;B;.

Vest4

0.10, 0.11

MutPred

0.32

.;Gain of phosphorylation at P1419 (P = 0.002);.;.;

MVP

0.068

MPC

1.2

ClinPred

0.041

GERP RS

0.63

Varity_R

0.045

gMVP

0.25

Mutation Taster

=98/2

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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7-78019428-G-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over