rs7812015

Positions:

• chr7-78127407-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_012301.4(MAGI2):​c.3213G>A​(p.Ser1071=) 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

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]

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt
MAGI2	NM_012301.4	c.3213G>A	p.Ser1071=	synonymous_variant	19/22	ENST00000354212.9	NP_036433.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAGI2	ENST00000354212.9	c.3213G>A	p.Ser1071=	synonymous_variant	19/22	1	NM_012301.4	ENSP00000346151	P4

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

GnomAD3 exomes AF: 0.813 AC: 196853 AN: 241984 Hom.: 81326 AF XY: 0.816 AC XY: 107180 AN XY: 131376

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 SAS exome AF: 0.776

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

Gnomad4 AFR exome AF: 0.913

Gnomad4 AMR exome AF: 0.707

Gnomad4 ASJ exome AF: 0.802

Gnomad4 EAS exome AF: 0.594

Gnomad4 SAS exome AF: 0.770

Gnomad4 FIN exome AF: 0.879

Gnomad4 NFE exome AF: 0.879

Gnomad4 OTH exome AF: 0.844

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

Gnomad4 AFR AF: 0.908

Gnomad4 AMR AF: 0.768

Gnomad4 ASJ AF: 0.795

Gnomad4 EAS AF: 0.589

Gnomad4 SAS AF: 0.764

Gnomad4 FIN AF: 0.870

Gnomad4 NFE AF: 0.876

Gnomad4 OTH AF: 0.846

Alfa AF: 0.857 Hom.: 58564

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

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 20, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 20, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jul 15, 2024	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. -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	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

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
CADD	Benign	5.6
DANN	Benign	0.61

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

Publications

LitVar

Other links and lift over

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