chr7-78019431-G-A

Variant names:

• chr7-78019431-G-A
• rs1306144777
• NM_012301.4:c.4252C>T

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.4252C>T​(p.Pro1418Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000288 in 1,041,130 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000014 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0000011 (0 hom.)
• Consequence: MAGI2 NM_012301.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0730
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07250908).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAGI2	NM_012301.4	c.4252C>T	p.Pro1418Ser	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.4252C>T	p.Pro1418Ser	missense_variant	Exon 22 of 22	1	NM_012301.4	ENSP00000346151.4

Frequencies

GnomAD3 genomes AF: 0.0000137 AC: 2 AN: 145612 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000246

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000153

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000112 AC: 1 AN: 895518 Hom.: 0 Cov.: 30 AF XY: 0.00000239 AC XY: 1 AN XY: 417996

African (AFR) AF: 0.00 AC: 0 AN: 17346

American (AMR) AF: 0.00 AC: 0 AN: 2798

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 7108

East Asian (EAS) AF: 0.00 AC: 0 AN: 9532

South Asian (SAS) AF: 0.00 AC: 0 AN: 17702

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5930

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1952

European-Non Finnish (NFE) AF: 0.00000125 AC: 1 AN: 802098

Other (OTH) AF: 0.00 AC: 0 AN: 31052

GnomAD4 genome AF: 0.0000137 AC: 2 AN: 145612 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 70800

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

African (AFR) AF: 0.0000246 AC: 1 AN: 40676

American (AMR) AF: 0.00 AC: 0 AN: 14730

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3392

East Asian (EAS) AF: 0.00 AC: 0 AN: 4976

South Asian (SAS) AF: 0.00 AC: 0 AN: 4800

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8254

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 304

European-Non Finnish (NFE) AF: 0.0000153 AC: 1 AN: 65558

Other (OTH) AF: 0.00 AC: 0 AN: 2014

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Nephrotic syndrome 15 Uncertain:1

Mar 07, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.050	T;T;.;.
Eigen	Benign	-0.90
Eigen_PC	Benign	-0.80
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.61	T;T;T;T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.073	T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.0	.;N;.;.
PhyloP100		-0.073
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	0.64	.;N;N;.
REVEL	Benign	0.023
Sift	Benign	0.49	.;T;T;.
Sift4G	Benign	0.56	T;T;T;T
Polyphen		0.0010	.;B;B;.
Vest4		0.15, 0.11
MutPred		0.31		.;Gain of phosphorylation at P1418 (P = 0.0022);.;.;
MVP		0.17
MPC		1.1
ClinPred		0.060	T
GERP RS		1.7
Varity_R		0.056
gMVP		0.18
Mutation Taster		=97/3	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: rs1306144777; hg19: chr7-77648748;