rs76346657

Positions:

• chr7-78178085-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_012301.4(MAGI2):​c.2329T>C​(p.Leu777=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00123 in 1,612,356 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0068 (11 hom., cov: 32)
  • Exomes 𝑓: 0.00066 (9 hom.)
• Consequence: MAGI2 NM_012301.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.00800

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 7-78178085-A-G is Benign according to our data. Variant chr7-78178085-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 129560.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.008 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00676 (1029/152286) while in subpopulation AFR AF= 0.0233 (968/41558). AF 95% confidence interval is 0.0221. There are 11 homozygotes in gnomad4. There are 492 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAGI2	NM_012301.4	c.2329T>C	p.Leu777=	synonymous_variant	14/22	ENST00000354212.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAGI2	ENST00000354212.9	c.2329T>C	p.Leu777=	synonymous_variant	14/22	1	NM_012301.4	P4

Frequencies

GnomAD3 genomes AF: 0.00678 AC: 1032 AN: 152168 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.0234

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00321

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: 0.0000735

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00177 AC: 444 AN: 250942 Hom.: 0 AF XY: 0.00131 AC XY: 178 AN XY: 135600

Gnomad AFR exome AF: 0.0237

Gnomad AMR exome AF: 0.00145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000265

Gnomad OTH exome AF: 0.000818

GnomAD4 exome AF: 0.000655 AC: 957 AN: 1460070 Hom.: 9 Cov.: 29 AF XY: 0.000529 AC XY: 384 AN XY: 726416

Gnomad4 AFR exome AF: 0.0240

Gnomad4 AMR exome AF: 0.00130

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000135

Gnomad4 OTH exome AF: 0.00118

GnomAD4 genome AF: 0.00676 AC: 1029 AN: 152286 Hom.: 11 Cov.: 32 AF XY: 0.00661 AC XY: 492 AN XY: 74452

Gnomad4 AFR AF: 0.0233

Gnomad4 AMR AF: 0.00321

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00311 Hom.: 2

Bravo AF: 0.00729

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.0000546

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 25, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 02, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -

not specified Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	4.9
DANN	Benign	0.66

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: rs76346657; hg19: chr7-77807402;