rs140954236
Positions:
Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_198576.4(AGRN):c.494C>T(p.Pro165Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000356 in 1,613,122 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.0019 ( 3 hom., cov: 32)
Exomes 𝑓: 0.00019 ( 0 hom. )
Consequence
AGRN
NM_198576.4 missense
NM_198576.4 missense
Scores
1
5
10
Clinical Significance
Conservation
PhyloP100: 0.00600
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 Benign. Variant got -20 ACMG points.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.006974727).
BP6
?
Variant 1-1035307-C-T is Benign according to our data. Variant chr1-1035307-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 474141.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
?
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00194 (295/152336) while in subpopulation AFR AF= 0.00685 (285/41578). AF 95% confidence interval is 0.0062. There are 3 homozygotes in gnomad4. There are 137 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
?
High Homozygotes in GnomAd4 at 3 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
AGRN | NM_198576.4 | c.494C>T | p.Pro165Leu | missense_variant | 3/36 | ENST00000379370.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
AGRN | ENST00000379370.7 | c.494C>T | p.Pro165Leu | missense_variant | 3/36 | 1 | NM_198576.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00192 AC: 292AN: 152218Hom.: 3 Cov.: 32
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GnomAD3 exomes AF: 0.000538 AC: 135AN: 250862Hom.: 1 AF XY: 0.000405 AC XY: 55AN XY: 135848
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GnomAD4 exome AF: 0.000192 AC: 280AN: 1460786Hom.: 0 Cov.: 33 AF XY: 0.000157 AC XY: 114AN XY: 726668
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GnomAD4 genome ? AF: 0.00194 AC: 295AN: 152336Hom.: 3 Cov.: 32 AF XY: 0.00184 AC XY: 137AN XY: 74494
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ClinVar
Significance: Likely benign
Submissions summary: Benign:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Oct 29, 2020 | See Variant Classification Assertion Criteria. - |
Congenital myasthenic syndrome 8 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 25, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Benign
T;T;.
MetaRNN
Benign
T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
N;.;.
MutationTaster
Benign
N
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;.;.
REVEL
Uncertain
Sift
Uncertain
D;.;.
Sift4G
Uncertain
D;T;.
Vest4
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