rs146185843
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Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_ModerateBP6BP7
The NM_198576.4(AGRN):c.1557C>T(p.Ala519=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000208 in 1,608,406 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00014 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00022 ( 0 hom. )
Consequence
AGRN
NM_198576.4 synonymous
NM_198576.4 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 1.04
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 Likely_benign. Variant got -2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.41).
BP6
Variant 1-1043411-C-T is Benign according to our data. Variant chr1-1043411-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 541213.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.
BP7
Synonymous conserved (PhyloP=1.04 with no splicing effect.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
AGRN | NM_198576.4 | c.1557C>T | p.Ala519= | synonymous_variant | 8/36 | ENST00000379370.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
AGRN | ENST00000379370.7 | c.1557C>T | p.Ala519= | synonymous_variant | 8/36 | 1 | NM_198576.4 | P1 | |
AGRN | ENST00000651234.1 | c.1242C>T | p.Ala414= | synonymous_variant | 7/38 | ||||
AGRN | ENST00000652369.1 | c.1242C>T | p.Ala414= | synonymous_variant | 7/35 | ||||
AGRN | ENST00000620552.4 | c.1143C>T | p.Ala381= | synonymous_variant | 8/39 | 5 |
Frequencies
GnomAD3 genomes AF: 0.000138 AC: 21AN: 152154Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000190 AC: 45AN: 237136Hom.: 0 AF XY: 0.000201 AC XY: 26AN XY: 129166
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GnomAD4 exome AF: 0.000216 AC: 314AN: 1456252Hom.: 0 Cov.: 35 AF XY: 0.000228 AC XY: 165AN XY: 724354
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GnomAD4 genome AF: 0.000138 AC: 21AN: 152154Hom.: 0 Cov.: 33 AF XY: 0.000148 AC XY: 11AN XY: 74328
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Congenital myasthenic syndrome 8 Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 18, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jun 07, 2021 | - - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2022 | AGRN: BP4, BP7 - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
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