7-78019354-G-A

Variant names:

• chr7-78019354-G-A
• rs13438302
• NM_012301.4:c.4329C>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_012301.4(MAGI2):​c.4329C>T​(p.Pro1443Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000221 in 1,359,434 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. P1443P) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: MAGI2 NM_012301.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.794
• Publications: 17 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: Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP7: Synonymous conserved (PhyloP=-0.794 with no splicing effect.

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.4329C>T	p.Pro1443Pro	synonymous	Exon 22 of 22	NP_036433.2
	MAGI2	NM_001301128.2		c.4287C>T	p.Pro1429Pro	synonymous	Exon 21 of 21	NP_001288057.1	Q86UL8-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAGI2	ENST00000354212.9	TSL:1 MANE Select	c.4329C>T	p.Pro1443Pro	synonymous	Exon 22 of 22	ENSP00000346151.4	Q86UL8-1
	MAGI2	ENST00000419488.5	TSL:1	c.4287C>T	p.Pro1429Pro	synonymous	Exon 21 of 21	ENSP00000405766.1	Q86UL8-2
	MAGI2	ENST00000522391.3	TSL:5	c.*566C>T		3_prime_UTR	Exon 23 of 23	ENSP00000428389.1	E7EWI0

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD2 exomes AF: 0.00000912 AC: 1 AN: 109592 AF XY: 0.0000162

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000136

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000221 AC: 3 AN: 1359434 Hom.: 0 Cov.: 32 AF XY: 0.00000298 AC XY: 2 AN XY: 671492

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 29060

American (AMR) AF: 0.00 AC: 0 AN: 32096

Ashkenazi Jewish (ASJ) AF: 0.0000409 AC: 1 AN: 24426

East Asian (EAS) AF: 0.00 AC: 0 AN: 31948

South Asian (SAS) AF: 0.00 AC: 0 AN: 76280

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33746

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5106

European-Non Finnish (NFE) AF: 0.00000187 AC: 2 AN: 1070122

Other (OTH) AF: 0.00 AC: 0 AN: 56650

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0225104), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 30

Alfa AF: 0.00 Hom.: 436

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	5.7
DANN	Benign	0.96
PhyloP100		-0.79

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: rs13438302; hg19: chr7-77648671;