rs952272424

Variant names:

• chr7-78019467-C-T
• rs952272424
• NM_012301.4:c.4216G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_012301.4(MAGI2):​c.4216G>A​(p.Ala1406Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000836 in 980,904 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00043 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000024 (0 hom.)
• Consequence: MAGI2 NM_012301.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.846
• 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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06004852).
• BP6: Variant 7-78019467-C-T is Benign according to our data. Variant chr7-78019467-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2902050.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAGI2	NM_012301.4	c.4216G>A	p.Ala1406Thr	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.4216G>A	p.Ala1406Thr	missense_variant	Exon 22 of 22	1	NM_012301.4	ENSP00000346151.4

Frequencies

GnomAD3 genomes AF: 0.000426 AC: 62 AN: 145564 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000136

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: 0.0000239 AC: 20 AN: 835340 Hom.: 0 Cov.: 30 AF XY: 0.0000259 AC XY: 10 AN XY: 386040

African (AFR) AF: 0.000885 AC: 14 AN: 15820

American (AMR) AF: 0.00 AC: 0 AN: 1044

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5176

East Asian (EAS) AF: 0.00 AC: 0 AN: 3684

South Asian (SAS) AF: 0.00 AC: 0 AN: 17106

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 362

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1630

European-Non Finnish (NFE) AF: 0.00000393 AC: 3 AN: 763140

Other (OTH) AF: 0.000110 AC: 3 AN: 27378

GnomAD4 genome AF: 0.000426 AC: 62 AN: 145564 Hom.: 0 Cov.: 30 AF XY: 0.000494 AC XY: 35 AN XY: 70790

African (AFR) AF: 0.00145 AC: 59 AN: 40712

American (AMR) AF: 0.000136 AC: 2 AN: 14708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3388

East Asian (EAS) AF: 0.00 AC: 0 AN: 5004

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8192

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 310

European-Non Finnish (NFE) AF: 0.0000153 AC: 1 AN: 65534

Other (OTH) AF: 0.00 AC: 0 AN: 2004

Alfa AF: 0.000356 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Oct 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	18
DANN	Benign	0.96
DEOGEN2	Benign	0.055	T;T;.;.
Eigen	Benign	-0.98
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.066	N
LIST_S2	Benign	0.50	T;T;T;T
M_CAP	Benign	0.070	D
MetaRNN	Benign	0.060	T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.34	.;N;.;.
PhyloP100		0.85
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	0.020	.;N;N;.
REVEL	Benign	0.028
Sift	Benign	0.47	.;T;T;.
Sift4G	Benign	0.61	T;T;T;T
Polyphen		0.0010	.;B;B;.
Vest4		0.064, 0.060
MutPred		0.26		.;Loss of helix (P = 0.0093);.;.;
MVP		0.13
MPC		1.1
ClinPred		0.074	T
GERP RS		2.4
Varity_R		0.033
gMVP		0.13
Mutation Taster		=95/5	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: rs952272424; hg19: chr7-77648784;