7-78019409-C-G

Variant names:

• chr7-78019409-C-G
• rs1053239653
• NM_012301.4:c.4274G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_012301.4(MAGI2):​c.4274G>C​(p.Arg1425Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000101 in 994,850 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. R1425H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000010 (0 hom.)
• Consequence: MAGI2 NM_012301.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.36
• 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31896755).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAGI2	NM_012301.4	c.4274G>C	p.Arg1425Pro	missense_variant	Exon 22 of 22	ENST00000354212.9	NP_036433.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAGI2	ENST00000354212.9	c.4274G>C	p.Arg1425Pro	missense_variant	Exon 22 of 22	1	NM_012301.4	ENSP00000346151.4

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000101 AC: 1 AN: 994850 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 469082

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

African (AFR) AF: 0.00 AC: 0 AN: 19980

American (AMR) AF: 0.00 AC: 0 AN: 5632

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10598

East Asian (EAS) AF: 0.00 AC: 0 AN: 19534

South Asian (SAS) AF: 0.00 AC: 0 AN: 18958

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 14298

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2438

European-Non Finnish (NFE) AF: 0.00000115 AC: 1 AN: 865888

Other (OTH) AF: 0.00 AC: 0 AN: 37524

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.097	T;T;.;.
Eigen	Benign	0.16
Eigen_PC	Benign	0.17
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.72	T;T;T;T
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.32	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.55	.;N;.;.
PhyloP100		5.4
PrimateAI	Pathogenic	0.93	D
PROVEAN	Uncertain	-2.4	.;N;N;.
REVEL	Benign	0.14
Sift	Uncertain	0.0030	.;D;D;.
Sift4G	Uncertain	0.0070	D;D;D;D
Polyphen		0.99, 0.99	.;D;D;.
Vest4		0.46, 0.42
MutPred		0.28		.;Loss of MoRF binding (P = 0.004);.;.;
MVP		0.068
MPC		1.5
ClinPred		0.94	D
GERP RS		3.5
Varity_R		0.43
gMVP		0.43
Mutation Taster		=49/51	disease causing

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: rs1053239653; hg19: chr7-77648726;