7-78078942-C-T

Variant names:

• chr7-78078942-C-T
• rs188293910
• ENST00000519748.5:c.2490G>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PP3_Moderate BP6 BS2

The NM_012301.4(MAGI2):​c.3706+5G>A variant causes a splice region, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000785 in 1,612,440 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00056 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00081 (2 hom.)
• Consequence: MAGI2 NM_012301.4 splice_region, intron
• Scores: Splicing: ADA: 0.9998
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: 7.75
• Publications: 0 publications found

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

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• BP6: Variant 7-78078942-C-T is Benign according to our data. Variant chr7-78078942-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 195607.
• BS2: High Homozygotes in GnomAdExome4 at 2 AD,AR gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAGI2	NM_012301.4	MANE Select	c.3706+5G>A		splice_region intron	N/A	NP_036433.2
	MAGI2	NM_001301128.2		c.3664+5G>A		splice_region intron	N/A	NP_001288057.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAGI2	ENST00000519748.5	TSL:1	c.2490G>A	p.Thr830Thr	synonymous	Exon 16 of 16	ENSP00000486774.1
	MAGI2	ENST00000354212.9	TSL:1 MANE Select	c.3706+5G>A		splice_region intron	N/A	ENSP00000346151.4
	MAGI2	ENST00000419488.5	TSL:1	c.3664+5G>A		splice_region intron	N/A	ENSP00000405766.1

Frequencies

GnomAD3 genomes AF: 0.000565 AC: 86 AN: 152108 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00106

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000526 AC: 131 AN: 249270 AF XY: 0.000483

Gnomad AFR exome AF: 0.000247

Gnomad AMR exome AF: 0.000294

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000546

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.000989

Gnomad OTH exome AF: 0.000492

GnomAD4 exome AF: 0.000808 AC: 1180 AN: 1460214 Hom.: 2 Cov.: 32 AF XY: 0.000761 AC XY: 553 AN XY: 726250

African (AFR) AF: 0.0000899 AC: 3 AN: 33372

American (AMR) AF: 0.000203 AC: 9 AN: 44266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26090

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.00 AC: 0 AN: 85622

European-Finnish (FIN) AF: 0.0000374 AC: 2 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00102 AC: 1132 AN: 1111676

Other (OTH) AF: 0.000564 AC: 34 AN: 60332

GnomAD4 genome AF: 0.000565 AC: 86 AN: 152226 Hom.: 0 Cov.: 32 AF XY: 0.000470 AC XY: 35 AN XY: 74434

African (AFR) AF: 0.000217 AC: 9 AN: 41530

American (AMR) AF: 0.000196 AC: 3 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00106 AC: 72 AN: 68008

Other (OTH) AF: 0.00 AC: 0 AN: 2108

Alfa AF: 0.000478 Hom.: 0

Bravo AF: 0.000525

EpiCase AF: 0.000545

EpiControl AF: 0.000771

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	3	not provided (5)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.15
CADD	Pathogenic	27
DANN	Benign	0.96
PhyloP100		7.8
Mutation Taster		=79/21	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs188293910; hg19: chr7-77708259;