NM_012301.4:c.3213G>A

Variant names:

• chr7-78127407-C-T
• rs7812015
• NM_012301.4:c.3213G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_012301.4(MAGI2):​c.3213G>A​(p.Ser1071Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.857 in 1,601,268 control chromosomes in the GnomAD database, including 591,156 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.86 (56215 hom., cov: 30)
  • Exomes 𝑓: 0.86 (534941 hom.)
• Consequence: MAGI2 NM_012301.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.549
• Publications: 19 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: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.34).
• BP6: Variant 7-78127407-C-T is Benign according to our data. Variant chr7-78127407-C-T is described in ClinVar as [Benign]. Clinvar id is 129564.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.549 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.901 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAGI2	NM_012301.4	c.3213G>A	p.Ser1071Ser	synonymous_variant	Exon 19 of 22	ENST00000354212.9	NP_036433.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAGI2	ENST00000354212.9	c.3213G>A	p.Ser1071Ser	synonymous_variant	Exon 19 of 22	1	NM_012301.4	ENSP00000346151.4

Frequencies

GnomAD3 genomes AF: 0.857 AC: 130215 AN: 152000 Hom.: 56167 Cov.: 30

Gnomad AFR AF: 0.908

Gnomad AMI AF: 0.693

Gnomad AMR AF: 0.768

Gnomad ASJ AF: 0.795

Gnomad EAS AF: 0.589

Gnomad SAS AF: 0.765

Gnomad FIN AF: 0.870

Gnomad MID AF: 0.801

Gnomad NFE AF: 0.876

Gnomad OTH AF: 0.845

GnomAD2 exomes AF: 0.813 AC: 196853 AN: 241984 AF XY: 0.816

Gnomad AFR exome AF: 0.911

Gnomad AMR exome AF: 0.697

Gnomad ASJ exome AF: 0.792

Gnomad EAS exome AF: 0.579

Gnomad FIN exome AF: 0.872

Gnomad NFE exome AF: 0.877

Gnomad OTH exome AF: 0.827

GnomAD4 exome AF: 0.857 AC: 1241572 AN: 1449150 Hom.: 534941 Cov.: 37 AF XY: 0.854 AC XY: 616274 AN XY: 721334

African (AFR) AF: 0.913 AC: 30555 AN: 33460

American (AMR) AF: 0.707 AC: 31607 AN: 44682

Ashkenazi Jewish (ASJ) AF: 0.802 AC: 20959 AN: 26120

East Asian (EAS) AF: 0.594 AC: 23552 AN: 39672

South Asian (SAS) AF: 0.770 AC: 66336 AN: 86206

European-Finnish (FIN) AF: 0.879 AC: 37306 AN: 42458

Middle Eastern (MID) AF: 0.802 AC: 4621 AN: 5762

European-Non Finnish (NFE) AF: 0.879 AC: 975762 AN: 1110534

Other (OTH) AF: 0.844 AC: 50874 AN: 60256

GnomAD4 genome AF: 0.857 AC: 130321 AN: 152118 Hom.: 56215 Cov.: 30 AF XY: 0.849 AC XY: 63102 AN XY: 74368

African (AFR) AF: 0.908 AC: 37701 AN: 41510

American (AMR) AF: 0.768 AC: 11741 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.795 AC: 2760 AN: 3472

East Asian (EAS) AF: 0.589 AC: 3032 AN: 5150

South Asian (SAS) AF: 0.764 AC: 3667 AN: 4798

European-Finnish (FIN) AF: 0.870 AC: 9213 AN: 10588

Middle Eastern (MID) AF: 0.786 AC: 231 AN: 294

European-Non Finnish (NFE) AF: 0.876 AC: 59561 AN: 68000

Other (OTH) AF: 0.846 AC: 1784 AN: 2108

Alfa AF: 0.858 Hom.: 75549

Bravo AF: 0.850

Asia WGS AF: 0.730 AC: 2542 AN: 3478

EpiCase AF: 0.858

EpiControl AF: 0.860

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Apr 20, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 20, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:2

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 92% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 86. Only high quality variants are reported. -

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Nephrotic syndrome 15 Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
CADD	Benign	5.6
DANN	Benign	0.61
PhyloP100		0.55
Mutation Taster		=81/19	polymorphism (auto)

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: rs7812015; hg19: chr7-77756724; COSMIC: COSV62650317;