rs117054456

Positions:

• chr7-78019768-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_012301.4(MAGI2):​c.3915G>A​(p.Gln1305=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.035 in 1,612,638 control chromosomes in the GnomAD database, including 1,238 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (79 hom., cov: 30)
  • Exomes 𝑓: 0.036 (1159 hom.)
• Consequence: MAGI2 NM_012301.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.30

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=-0.29).
• BP6: Variant 7-78019768-C-T is Benign according to our data. Variant chr7-78019768-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 95512.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-78019768-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=2.3 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0251 (3807/151934) while in subpopulation NFE AF= 0.0409 (2779/67902). AF 95% confidence interval is 0.0397. There are 79 homozygotes in gnomad4. There are 1748 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 79 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAGI2	NM_012301.4	c.3915G>A	p.Gln1305=	synonymous_variant	22/22	ENST00000354212.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAGI2	ENST00000354212.9	c.3915G>A	p.Gln1305=	synonymous_variant	22/22	1	NM_012301.4	P4

Frequencies

GnomAD3 genomes AF: 0.0251 AC: 3809 AN: 151822 Hom.: 79 Cov.: 30

Gnomad AFR AF: 0.00814

Gnomad AMI AF: 0.0471

Gnomad AMR AF: 0.0223

Gnomad ASJ AF: 0.0208

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00973

Gnomad FIN AF: 0.0110

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0409

Gnomad OTH AF: 0.0297

GnomAD3 exomes AF: 0.0252 AC: 6243 AN: 247638 Hom.: 124 AF XY: 0.0256 AC XY: 3435 AN XY: 134092

Gnomad AFR exome AF: 0.00842

Gnomad AMR exome AF: 0.0170

Gnomad ASJ exome AF: 0.0202

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.00951

Gnomad FIN exome AF: 0.0118

Gnomad NFE exome AF: 0.0416

Gnomad OTH exome AF: 0.0261

GnomAD4 exome AF: 0.0360 AC: 52650 AN: 1460704 Hom.: 1159 Cov.: 32 AF XY: 0.0355 AC XY: 25801 AN XY: 726516

Gnomad4 AFR exome AF: 0.00687

Gnomad4 AMR exome AF: 0.0168

Gnomad4 ASJ exome AF: 0.0208

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0101

Gnomad4 FIN exome AF: 0.0116

Gnomad4 NFE exome AF: 0.0429

Gnomad4 OTH exome AF: 0.0304

GnomAD4 genome AF: 0.0251 AC: 3807 AN: 151934 Hom.: 79 Cov.: 30 AF XY: 0.0235 AC XY: 1748 AN XY: 74290

Gnomad4 AFR AF: 0.00812

Gnomad4 AMR AF: 0.0222

Gnomad4 ASJ AF: 0.0208

Gnomad4 EAS AF: 0.000195

Gnomad4 SAS AF: 0.00974

Gnomad4 FIN AF: 0.0110

Gnomad4 NFE AF: 0.0409

Gnomad4 OTH AF: 0.0294

Alfa AF: 0.0312 Hom.: 29

Bravo AF: 0.0257

EpiCase AF: 0.0402

EpiControl AF: 0.0457

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 30, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 29, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 05, 2012	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 14, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.29
CADD	Benign	12
DANN	Benign	0.96

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: rs117054456; hg19: chr7-77649085; COSMIC: COSV62680531; COSMIC: COSV62680531;