Genetic Variant MAGI2:c.2048-8000G>C (chr7-78209193-C-G) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_012301.4(MAGI2):c.2048-8000G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.090 ( 274 hom., cov: 4)

Consequence

MAGI2
NM_012301.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.838

Publications

2 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:

LOC124901684 (HGNC:):

LOC124901684 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.98).

BS2

High Homozygotes in GnomAd4 at 274 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAGI2	NM_012301.4 link	c.2048-8000G>C		intron_variant	Intron 10 of 21	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.2048-8000G>C		intron_variant	Intron 10 of 21	1	NM_012301.4	ENSP00000346151.4		Q86UL8-1

Frequencies

GnomAD3 genomes

AF:

0.0897

AC:

2654

AN:

29600

Hom.:

274

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0374

Gnomad AMI

AF:

0.0547

Gnomad AMR

AF:

0.0664

Gnomad ASJ

AF:

0.186

Gnomad EAS

AF:

0.0528

Gnomad SAS

AF:

0.0482

Gnomad FIN

AF:

0.0281

Gnomad MID

AF:

0.0625

Gnomad NFE

AF:

0.153

Gnomad OTH

AF:

0.112

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.0896

AC:

2654

AN:

29630

Hom.:

274

Cov.:

AF XY:

0.0843

AC XY:

1169

AN XY:

13872

show subpopulations

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

African (AFR)

AF:

0.0373

AC:

487

AN:

13044

American (AMR)

AF:

0.0663

AC:

139

AN:

2098

Ashkenazi Jewish (ASJ)

AF:

0.186

AC:

150

AN:

806

East Asian (EAS)

AF:

0.0529

AC:

AN:

832

South Asian (SAS)

AF:

0.0485

AC:

AN:

392

European-Finnish (FIN)

AF:

0.0281

AC:

AN:

498

Middle Eastern (MID)

AF:

0.0588

AC:

AN:

European-Non Finnish (NFE)

AF:

0.153

AC:

1755

AN:

11466

Other (OTH)

AF:

0.111

AC:

AN:

332

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.371

Heterozygous variant carriers

124

247

371

494

618

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.98

CADD

Benign

3.1

(source)

DANN

Benign

0.72

PhyloP100

-0.84

Mutation Taster

=100/0

polymorphism (auto)

(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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over