NM_012301.4:c.4269G>C

Variant names:

• chr7-78019414-C-G
• rs2960452
• NM_012301.4:c.4269G>C

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.4269G>C​(p.Pro1423Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.215 in 1,128,038 control chromosomes in the GnomAD database, including 30,428 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (6856 hom., cov: 29)
  • Exomes 𝑓: 0.21 (23572 hom.)
• Consequence: MAGI2 NM_012301.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.15
• Publications: 6 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=-0.74).
• BP6: Variant 7-78019414-C-G is Benign according to our data. Variant chr7-78019414-C-G is described in ClinVar as Benign. ClinVar VariationId is 95513.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.15 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.543 is higher than 0.05.

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.4269G>C	p.Pro1423Pro	synonymous	Exon 22 of 22	NP_036433.2
	MAGI2	NM_001301128.2		c.4227G>C	p.Pro1409Pro	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.4269G>C	p.Pro1423Pro	synonymous	Exon 22 of 22	ENSP00000346151.4
	MAGI2	ENST00000419488.5	TSL:1	c.4227G>C	p.Pro1409Pro	synonymous	Exon 21 of 21	ENSP00000405766.1
	MAGI2	ENST00000522391.3	TSL:5	c.*506G>C		3_prime_UTR	Exon 23 of 23	ENSP00000428389.1

Frequencies

GnomAD3 genomes AF: 0.283 AC: 41184 AN: 145556 Hom.: 6851 Cov.: 29

Gnomad AFR AF: 0.404

Gnomad AMI AF: 0.210

Gnomad AMR AF: 0.309

Gnomad ASJ AF: 0.273

Gnomad EAS AF: 0.561

Gnomad SAS AF: 0.352

Gnomad FIN AF: 0.243

Gnomad MID AF: 0.265

Gnomad NFE AF: 0.184

Gnomad OTH AF: 0.253

GnomAD2 exomes AF: 0.349 AC: 259 AN: 742 AF XY: 0.362

Gnomad AFR exome AF: 0.500

Gnomad AMR exome AF: 0.569

Gnomad ASJ exome AF: 0.313

Gnomad EAS exome AF: 0.500

Gnomad FIN exome AF: 0.324

Gnomad NFE exome AF: 0.269

Gnomad OTH exome AF: 0.458

GnomAD4 exome AF: 0.205 AC: 201647 AN: 982416 Hom.: 23572 Cov.: 30 AF XY: 0.205 AC XY: 95060 AN XY: 462686

African (AFR) AF: 0.420 AC: 8306 AN: 19754

American (AMR) AF: 0.373 AC: 1947 AN: 5224

Ashkenazi Jewish (ASJ) AF: 0.277 AC: 2821 AN: 10178

East Asian (EAS) AF: 0.593 AC: 11074 AN: 18670

South Asian (SAS) AF: 0.338 AC: 6312 AN: 18690

European-Finnish (FIN) AF: 0.226 AC: 2964 AN: 13136

Middle Eastern (MID) AF: 0.249 AC: 593 AN: 2378

European-Non Finnish (NFE) AF: 0.185 AC: 158436 AN: 857672

Other (OTH) AF: 0.250 AC: 9194 AN: 36714

GnomAD4 genome AF: 0.283 AC: 41214 AN: 145622 Hom.: 6856 Cov.: 29 AF XY: 0.288 AC XY: 20434 AN XY: 70856

African (AFR) AF: 0.404 AC: 16384 AN: 40588

American (AMR) AF: 0.309 AC: 4575 AN: 14782

Ashkenazi Jewish (ASJ) AF: 0.273 AC: 928 AN: 3400

East Asian (EAS) AF: 0.560 AC: 2749 AN: 4906

South Asian (SAS) AF: 0.353 AC: 1670 AN: 4736

European-Finnish (FIN) AF: 0.243 AC: 2028 AN: 8344

Middle Eastern (MID) AF: 0.257 AC: 71 AN: 276

European-Non Finnish (NFE) AF: 0.184 AC: 12097 AN: 65640

Other (OTH) AF: 0.255 AC: 523 AN: 2052

Alfa AF: 0.238 Hom.: 619

Bravo AF: 0.295

Asia WGS AF: 0.438 AC: 1421 AN: 3254

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	5.9
DANN	Benign	0.82
PhyloP100		-1.1
Mutation Taster		=95/5	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: rs2960452; hg19: chr7-77648731; COSMIC: COSV62634115; COSMIC: COSV62634115;