chr7-78019385-GGCCCCGGCGCGACGGCGGCCTTGCGCGCCGGGGC-G

Position:

• chr7-78019385-GGCCCCGGCGCGACGGCGGCCTTGCGCGCCGGGGC-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The NM_012301.4(MAGI2):​c.4264_4297del​(p.Ala1422ProfsTer41) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000182 in 1,100,316 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000018 (0 hom.)
• Consequence: MAGI2 NM_012301.4 frameshift
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.98

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 Uncertain_significance. Variant got 4 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0238 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAGI2	NM_012301.4	c.4264_4297del	p.Ala1422ProfsTer41	frameshift_variant	22/22	ENST00000354212.9	NP_036433.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAGI2	ENST00000354212.9	c.4264_4297del	p.Ala1422ProfsTer41	frameshift_variant	22/22	1	NM_012301.4	ENSP00000346151	P4

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000182 AC: 2 AN: 1100316 Hom.: 0 AF XY: 0.00000190 AC XY: 1 AN XY: 525976

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000372

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000107

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Nephrotic syndrome 15 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

3billion

May 22, 2022

The variant is not observed in the gnomAD v2.1.1 dataset. Frameshift: predicted to result in a loss or disruption of normal protein function through protein truncation. The predicted truncated protein may be shortened by less than 10%. Therefore, this variant is classified as uncertain significanceaccording to the recommendation of ACMG/AMP guideline. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1808058702; hg19: chr7-77648702;