rs117054456

Variant names:

• chr7-78019768-C-T
• rs117054456
• NM_012301.4:c.3915G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_012301.4(MAGI2):​c.3915G>A​(p.Gln1305Gln) 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:6
• Conservation: PhyloP100: 2.30
• Publications: 5 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=-0.29).
• BP6: Variant 7-78019768-C-T is Benign according to our data. Variant chr7-78019768-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 95512.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 79 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012301.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAGI2	NM_012301.4	MANE Select	c.3915G>A	p.Gln1305Gln	synonymous	Exon 22 of 22	NP_036433.2
	MAGI2	NM_001301128.2		c.3873G>A	p.Gln1291Gln	synonymous	Exon 21 of 21	NP_001288057.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAGI2	ENST00000354212.9	TSL:1 MANE Select	c.3915G>A	p.Gln1305Gln	synonymous	Exon 22 of 22	ENSP00000346151.4
	MAGI2	ENST00000419488.5	TSL:1	c.3873G>A	p.Gln1291Gln	synonymous	Exon 21 of 21	ENSP00000405766.1
	MAGI2	ENST00000522391.3	TSL:5	c.*152G>A		3_prime_UTR	Exon 23 of 23	ENSP00000428389.1

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

GnomAD2 exomes AF: 0.0252 AC: 6243 AN: 247638 AF XY: 0.0256

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 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

African (AFR) AF: 0.00687 AC: 230 AN: 33468

American (AMR) AF: 0.0168 AC: 751 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0208 AC: 543 AN: 26124

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39676

South Asian (SAS) AF: 0.0101 AC: 875 AN: 86238

European-Finnish (FIN) AF: 0.0116 AC: 612 AN: 52538

Middle Eastern (MID) AF: 0.0267 AC: 154 AN: 5766

European-Non Finnish (NFE) AF: 0.0429 AC: 47645 AN: 1111802

Other (OTH) AF: 0.0304 AC: 1837 AN: 60374

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

African (AFR) AF: 0.00812 AC: 337 AN: 41504

American (AMR) AF: 0.0222 AC: 340 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0208 AC: 72 AN: 3462

East Asian (EAS) AF: 0.000195 AC: 1 AN: 5136

South Asian (SAS) AF: 0.00974 AC: 47 AN: 4826

European-Finnish (FIN) AF: 0.0110 AC: 116 AN: 10504

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0409 AC: 2779 AN: 67902

Other (OTH) AF: 0.0294 AC: 62 AN: 2112

Alfa AF: 0.0357 Hom.: 167

Bravo AF: 0.0257

EpiCase AF: 0.0402

EpiControl AF: 0.0457

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.29
CADD	Benign	12
DANN	Benign	0.96
PhyloP100		2.3
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: rs117054456; hg19: chr7-77649085; COSMIC: COSV62680531; COSMIC: COSV62680531;