Genetic Variant MAGI2:p.Gly1396del (chr7-78019494-TGCC-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PM4_Supporting

The NM_012301.4(MAGI2):c.4186_4188delGGC(p.Gly1396del) variant causes a conservative inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000012 in 834,646 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 30)

Exomes 𝑓: 0.0000012 ( 0 hom. )

Consequence

MAGI2
NM_012301.4 conservative_inframe_deletion

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.249

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: Labcorp Genetics (formerly Invitae), Ambry Genetics
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 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM4

Nonframeshift variant in NON repetitive region in NM_012301.4. Strenght limited to Supporting due to length of the change: 1aa.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012301.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAGI2	NM_012301.4	MANE Select	c.4186_4188delGGC	p.Gly1396del	conservative_inframe_deletion	Exon 22 of 22	NP_036433.2
	MAGI2	NM_001301128.2		c.4144_4146delGGC	p.Gly1382del	conservative_inframe_deletion	Exon 21 of 21	NP_001288057.1	Q86UL8-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MAGI2	ENST00000354212.9	TSL:1 MANE Select	c.4186_4188delGGC	p.Gly1396del	conservative_inframe_deletion	Exon 22 of 22	ENSP00000346151.4	Q86UL8-1
MAGI2	ENST00000419488.5	TSL:1	c.4144_4146delGGC	p.Gly1382del	conservative_inframe_deletion	Exon 21 of 21	ENSP00000405766.1	Q86UL8-2
MAGI2	ENST00000522391.3	TSL:5	c.423_425delGGC		3_prime_UTR	Exon 23 of 23	ENSP00000428389.1	E7EWI0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

AF XY:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

GnomAD4 exome

AF:

0.00000120

AC:

AN:

834646

Hom.:

AF XY:

0.00000259

AC XY:

AN XY:

385726

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

15792

American (AMR)

AF:

0.00

AC:

AN:

1002

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

5164

East Asian (EAS)

AF:

0.00

AC:

AN:

3688

South Asian (SAS)

AF:

0.00

AC:

AN:

17132

European-Finnish (FIN)

AF:

0.00

AC:

AN:

288

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1620

European-Non Finnish (NFE)

AF:

0.00000131

AC:

AN:

762630

Other (OTH)

AF:

0.00

AC:

AN:

27330

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 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: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.25

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over