7-78501664-G-C

Variant names:

• chr7-78501664-G-C
• rs587780389
• NM_012301.4:c.878C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_012301.4(MAGI2):​c.878C>G​(p.Thr293Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 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. T293I) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MAGI2 NM_012301.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.32
• Publications: 1 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: 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=0.098353595).

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.878C>G	p.Thr293Ser	missense	Exon 5 of 22	NP_036433.2
	MAGI2	NM_001301128.2		c.878C>G	p.Thr293Ser	missense	Exon 5 of 21	NP_001288057.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAGI2	ENST00000354212.9	TSL:1 MANE Select	c.878C>G	p.Thr293Ser	missense	Exon 5 of 22	ENSP00000346151.4
	MAGI2	ENST00000419488.5	TSL:1	c.878C>G	p.Thr293Ser	missense	Exon 5 of 21	ENSP00000405766.1
	MAGI2	ENST00000522391.3	TSL:5	c.878C>G	p.Thr293Ser	missense	Exon 5 of 23	ENSP00000428389.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	18
DANN	Benign	0.68
DEOGEN2	Benign	0.060	T
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.44	N
LIST_S2	Benign	0.60	T
M_CAP	Benign	0.0042	T
MetaRNN	Benign	0.098	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.1	L
PhyloP100		3.3
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.35	N
REVEL	Benign	0.070
Sift	Benign	0.74	T
Sift4G	Benign	0.53	T
Polyphen		0.0010	B
Vest4		0.18
MutPred		0.23		Loss of methylation at K291 (P = 0.1068)
MVP		0.16
MPC		0.18
ClinPred		0.23	T
GERP RS		5.0
Varity_R		0.051
gMVP		0.19
Mutation Taster		=79/21	polymorphism

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

Other links and lift over

dbSNP: rs587780389; hg19: chr7-78130981;