rs757879583
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_198576.4(AGRN):c.2182G>A(p.Glu728Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000018 in 1,612,634 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E728V) has been classified as Benign.
Frequency
Genomes: 𝑓 0.000072 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000012 ( 0 hom. )
Consequence
AGRN
NM_198576.4 missense
NM_198576.4 missense
Scores
1
8
8
Clinical Significance
Conservation
PhyloP100: 7.18
Genes affected
AGRN (HGNC:329): (agrin) This gene encodes one of several proteins that are critical in the development of the neuromuscular junction (NMJ), as identified in mouse knock-out studies. The encoded protein contains several laminin G, Kazal type serine protease inhibitor, and epidermal growth factor domains. Additional post-translational modifications occur to add glycosaminoglycans and disulfide bonds. In one family with congenital myasthenic syndrome affecting limb-girdle muscles, a mutation in this gene was found. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Mar 2015]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
AGRN | NM_198576.4 | c.2182G>A | p.Glu728Lys | missense_variant | 12/36 | ENST00000379370.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
AGRN | ENST00000379370.7 | c.2182G>A | p.Glu728Lys | missense_variant | 12/36 | 1 | NM_198576.4 | P1 | |
AGRN | ENST00000651234.1 | c.1867G>A | p.Glu623Lys | missense_variant | 11/38 | ||||
AGRN | ENST00000652369.1 | c.1867G>A | p.Glu623Lys | missense_variant | 11/35 | ||||
AGRN | ENST00000620552.4 | c.1768G>A | p.Glu590Lys | missense_variant | 12/39 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000723 AC: 11AN: 152192Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000241 AC: 6AN: 249152Hom.: 0 AF XY: 0.0000222 AC XY: 3AN XY: 135302
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GnomAD4 exome AF: 0.0000123 AC: 18AN: 1460442Hom.: 0 Cov.: 35 AF XY: 0.00000963 AC XY: 7AN XY: 726560
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GnomAD4 genome ? AF: 0.0000723 AC: 11AN: 152192Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3AN XY: 74340
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Congenital myasthenic syndrome 8 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | May 25, 2022 | This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 728 of the AGRN protein (p.Glu728Lys). This variant is present in population databases (rs757879583, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with AGRN-related conditions. ClinVar contains an entry for this variant (Variation ID: 541159). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D
M_CAP
Benign
D
MetaRNN
Uncertain
D;D
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;.
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;.
REVEL
Benign
Sift
Benign
T;.
Sift4G
Uncertain
D;D
Vest4
MutPred
Gain of methylation at E728 (P = 0.0115);.;
MVP
MPC
ClinPred
T
GERP RS
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at