7-78019216-C-T

Variant names:

• chr7-78019216-C-T
• rs77802301
• NM_012301.4:c.*99G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BS1 BS2

The NM_012301.4(MAGI2):​c.*99G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.002 in 1,375,632 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.010 (24 hom., cov: 32)
  • Exomes 𝑓: 0.00095 (21 hom.)
• Consequence: MAGI2 NM_012301.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.713
• Publications: 1 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 7-78019216-C-T is Benign according to our data. Variant chr7-78019216-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 1317281.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0104 (1588/152262) while in subpopulation AFR AF = 0.036 (1495/41564). AF 95% confidence interval is 0.0345. There are 24 homozygotes in GnomAd4. There are 758 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 24 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAGI2	NM_012301.4	c.*99G>A		3_prime_UTR_variant	Exon 22 of 22	ENST00000354212.9	NP_036433.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAGI2	ENST00000354212.9	c.*99G>A		3_prime_UTR_variant	Exon 22 of 22	1	NM_012301.4	ENSP00000346151.4

Frequencies

GnomAD3 genomes AF: 0.0104 AC: 1588 AN: 152144 Hom.: 24 Cov.: 32

Gnomad AFR AF: 0.0361

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00412

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.0115

GnomAD2 exomes AF: 0.00176 AC: 198 AN: 112358 AF XY: 0.00130

Gnomad AFR exome AF: 0.0404

Gnomad AMR exome AF: 0.00184

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000855

Gnomad OTH exome AF: 0.00248

GnomAD4 exome AF: 0.000946 AC: 1157 AN: 1223370 Hom.: 21 Cov.: 17 AF XY: 0.000799 AC XY: 488 AN XY: 610546

African (AFR) AF: 0.0360 AC: 958 AN: 26648

American (AMR) AF: 0.00228 AC: 72 AN: 31524

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23614

East Asian (EAS) AF: 0.00 AC: 0 AN: 30930

South Asian (SAS) AF: 0.00 AC: 0 AN: 73186

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33584

Middle Eastern (MID) AF: 0.00131 AC: 7 AN: 5348

European-Non Finnish (NFE) AF: 0.0000201 AC: 19 AN: 946388

Other (OTH) AF: 0.00194 AC: 101 AN: 52148

GnomAD4 genome AF: 0.0104 AC: 1588 AN: 152262 Hom.: 24 Cov.: 32 AF XY: 0.0102 AC XY: 758 AN XY: 74462

African (AFR) AF: 0.0360 AC: 1495 AN: 41564

American (AMR) AF: 0.00412 AC: 63 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5156

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68026

Other (OTH) AF: 0.0114 AC: 24 AN: 2108

Alfa AF: 0.00632 Hom.: 0

Bravo AF: 0.0121

ExAC AF: 0.00147 AC: 158

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Feb 24, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	18
DANN	Benign	0.96
FATHMM_MKL	Benign	0.57	D
PhyloP100		0.71
GERP RS		3.4
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs77802301; hg19: chr7-77648533;