rs2074641

Variant names:

• chr7-78127263-T-C
• rs2074641
• NM_012301.4:c.3357A>G

Your query was ambiguous. Multiple possible variants found:

• chr7-78127263-T-C
• chr7-78127263-T-G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_012301.4(MAGI2):​c.3357A>G​(p.Leu1119Leu) 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 1,610,004 control chromosomes in the GnomAD database, including 594,423 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.86 (56239 hom., cov: 31)
  • Exomes 𝑓: 0.86 (538184 hom.)
• Consequence: MAGI2 NM_012301.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.466
• Publications: 17 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 7-78127263-T-C is Benign according to our data. Variant chr7-78127263-T-C is described in ClinVar as Benign. ClinVar VariationId is 129565.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.466 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.9 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAGI2	NM_012301.4	c.3357A>G	p.Leu1119Leu	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.3357A>G	p.Leu1119Leu	synonymous_variant	Exon 19 of 22	1	NM_012301.4	ENSP00000346151.4

Frequencies

GnomAD3 genomes AF: 0.857 AC: 130250 AN: 152032 Hom.: 56191 Cov.: 31

Gnomad AFR AF: 0.908

Gnomad AMI AF: 0.694

Gnomad AMR AF: 0.768

Gnomad ASJ AF: 0.795

Gnomad EAS AF: 0.589

Gnomad SAS AF: 0.764

Gnomad FIN AF: 0.870

Gnomad MID AF: 0.801

Gnomad NFE AF: 0.876

Gnomad OTH AF: 0.845

GnomAD2 exomes AF: 0.815 AC: 201791 AN: 247526 AF XY: 0.817

Gnomad AFR exome AF: 0.912

Gnomad AMR exome AF: 0.696

Gnomad ASJ exome AF: 0.791

Gnomad EAS exome AF: 0.579

Gnomad FIN exome AF: 0.872

Gnomad NFE exome AF: 0.877

Gnomad OTH exome AF: 0.829

GnomAD4 exome AF: 0.857 AC: 1249121 AN: 1457854 Hom.: 538184 Cov.: 57 AF XY: 0.854 AC XY: 619599 AN XY: 725136

African (AFR) AF: 0.913 AC: 30400 AN: 33282

American (AMR) AF: 0.707 AC: 31082 AN: 43940

Ashkenazi Jewish (ASJ) AF: 0.802 AC: 20690 AN: 25800

East Asian (EAS) AF: 0.594 AC: 23515 AN: 39610

South Asian (SAS) AF: 0.769 AC: 66076 AN: 85880

European-Finnish (FIN) AF: 0.876 AC: 46601 AN: 53170

Middle Eastern (MID) AF: 0.801 AC: 4576 AN: 5712

European-Non Finnish (NFE) AF: 0.878 AC: 975358 AN: 1110268

Other (OTH) AF: 0.844 AC: 50823 AN: 60192

GnomAD4 genome AF: 0.857 AC: 130356 AN: 152150 Hom.: 56239 Cov.: 31 AF XY: 0.849 AC XY: 63100 AN XY: 74356

African (AFR) AF: 0.908 AC: 37713 AN: 41526

American (AMR) AF: 0.768 AC: 11734 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.795 AC: 2756 AN: 3468

East Asian (EAS) AF: 0.589 AC: 3030 AN: 5144

South Asian (SAS) AF: 0.764 AC: 3668 AN: 4804

European-Finnish (FIN) AF: 0.870 AC: 9230 AN: 10604

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

European-Non Finnish (NFE) AF: 0.876 AC: 59574 AN: 68012

Other (OTH) AF: 0.847 AC: 1787 AN: 2110

Alfa AF: 0.864 Hom.: 219114

Bravo AF: 0.850

Asia WGS AF: 0.730 AC: 2542 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

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

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:2

-

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. -

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. -

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	-0.51
CADD	Benign	6.9
DANN	Benign	0.75
PhyloP100		0.47
Mutation Taster		=100/0	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: rs2074641; hg19: chr7-77756580; COSMIC: COSV62668799;