Genetic Variant NM_012301.4:c.4252C>T (chr7-78019431-G-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.4252C>T(p.Pro1418Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000288 in 1,041,130 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. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

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

Exomes 𝑓: 0.0000011 ( 0 hom. )

Consequence

MAGI2
NM_012301.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0730

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=0.07250908).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAGI2	NM_012301.4 link	c.4252C>T	p.Pro1418Ser	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.4252C>T	p.Pro1418Ser	missense_variant	Exon 22 of 22	1	NM_012301.4	ENSP00000346151.4		Q86UL8-1

Frequencies

GnomAD3 genomes

AF:

0.0000137

AC:

AN:

145612

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000246

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000153

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000112

AC:

AN:

895518

Hom.:

Cov.:

AF XY:

0.00000239

AC XY:

AN XY:

417996

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

17346

American (AMR)

AF:

0.00

AC:

AN:

2798

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

7108

East Asian (EAS)

AF:

0.00

AC:

AN:

9532

South Asian (SAS)

AF:

0.00

AC:

AN:

17702

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5930

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1952

European-Non Finnish (NFE)

AF:

0.00000125

AC:

AN:

802098

Other (OTH)

AF:

0.00

AC:

AN:

31052

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000137

AC:

AN:

145612

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

70800

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000246

AC:

AN:

40676

American (AMR)

AF:

0.00

AC:

AN:

14730

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3392

East Asian (EAS)

AF:

0.00

AC:

AN:

4976

South Asian (SAS)

AF:

0.00

AC:

AN:

4800

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8254

Middle Eastern (MID)

AF:

0.00

AC:

AN:

304

European-Non Finnish (NFE)

AF:

0.0000153

AC:

AN:

65558

Other (OTH)

AF:

0.00

AC:

AN:

2014

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.350

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Nephrotic syndrome 15

Uncertain:1

Mar 07, 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

0.078

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.64

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.050

T;T;.;.

Eigen

Benign

-0.90

Eigen_PC

Benign

-0.80

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.61

T;T;T;T

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.073

T;T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.0

.;N;.;.

PhyloP100

-0.073

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

0.64

.;N;N;.

REVEL

Benign

0.023

Sift

Benign

0.49

.;T;T;.

Sift4G

Benign

0.56

T;T;T;T

Polyphen

0.0010

.;B;B;.

Vest4

0.15, 0.11

MutPred

0.31

.;Gain of phosphorylation at P1418 (P = 0.0022);.;.;

MVP

0.17

MPC

1.1

ClinPred

0.060

GERP RS

1.7

Varity_R

0.056

gMVP

0.18

Mutation Taster

=97/3

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.4252C>T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over