rs538792693
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong
The NM_198576.4(AGRN):c.5332G>A(p.Ala1778Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000113 in 1,568,640 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. A1778A) has been classified as Likely benign.
Frequency
Consequence
NM_198576.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
AGRN | NM_198576.4 | c.5332G>A | p.Ala1778Thr | missense_variant | 31/36 | ENST00000379370.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
AGRN | ENST00000379370.7 | c.5332G>A | p.Ala1778Thr | missense_variant | 31/36 | 1 | NM_198576.4 | P1 | |
AGRN | ENST00000651234.1 | c.5029G>A | p.Ala1677Thr | missense_variant | 31/38 | ||||
AGRN | ENST00000652369.1 | c.5017G>A | p.Ala1673Thr | missense_variant | 30/35 | ||||
AGRN | ENST00000620552.4 | c.4930G>A | p.Ala1644Thr | missense_variant | 32/39 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000789 AC: 12AN: 152110Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000262 AC: 46AN: 175366Hom.: 1 AF XY: 0.000351 AC XY: 33AN XY: 93952
GnomAD4 exome AF: 0.000116 AC: 165AN: 1416412Hom.: 1 Cov.: 36 AF XY: 0.000170 AC XY: 119AN XY: 700254
GnomAD4 genome ? AF: 0.0000788 AC: 12AN: 152228Hom.: 0 Cov.: 33 AF XY: 0.000121 AC XY: 9AN XY: 74424
ClinVar
Submissions by phenotype
Congenital myasthenic syndrome 8 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jul 04, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 26, 2022 | This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1778 of the AGRN protein (p.Ala1778Thr). This variant is present in population databases (rs538792693, gnomAD 0.2%). 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: 474150). 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: "Probably 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. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 10, 2023 | Variant summary: AGRN c.5332G>A (p.Ala1778Thr) results in a non-conservative amino acid change located in the Laminin G domain (IPR001791) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00026 in 175366 control chromosomes in the gnomAD database, including 1 homozygote. To our knowledge, no occurrence of c.5332G>A in individuals affected with Congenital Myasthenic Syndrome-8 and no experimental evidence demonstrating its impact on protein function have been reported. One submitter has cited a clinical-significance assessment for this variant to ClinVar after 2014 and has classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at