chr1-1020195-G-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_198576.4(AGRN):ā€‹c.23G>Cā€‹(p.Gly8Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: not found (cov: 31)
Exomes š‘“: 0.0 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

AGRN
NM_198576.4 missense

Scores

2
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.340
Variant links:
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]

Genome browser will be placed here

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 (MetaRNN=0.043292403).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
AGRNNM_198576.4 linkuse as main transcriptc.23G>C p.Gly8Ala missense_variant 1/36 ENST00000379370.7 NP_940978.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
AGRNENST00000379370.7 linkuse as main transcriptc.23G>C p.Gly8Ala missense_variant 1/361 NM_198576.4 ENSP00000368678 P1O00468-6
AGRNENST00000620552.4 linkuse as main transcriptc.-392G>C 5_prime_UTR_variant 1/395 ENSP00000484607

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
1209480
Hom.:
0
Cov.:
29
AF XY:
0.00
AC XY:
0
AN XY:
592398
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
31

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 submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpMay 10, 2022This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 8 of the AGRN protein (p.Gly8Ala). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with AGRN-related conditions. 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: "Tolerated"; PolyPhen-2: "Not Available"; 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
-0.21
T
BayesDel_noAF
Benign
-0.54
CADD
Benign
3.8
DANN
Benign
0.28
Eigen
Benign
-1.7
Eigen_PC
Benign
-1.7
FATHMM_MKL
Benign
0.0022
N
LIST_S2
Benign
0.36
T
M_CAP
Pathogenic
0.32
D
MetaRNN
Benign
0.043
T
MetaSVM
Benign
-0.86
T
MutationAssessor
Benign
-0.23
N
MutationTaster
Benign
1.0
N
PrimateAI
Pathogenic
0.82
D
PROVEAN
Benign
0.34
N
REVEL
Benign
0.071
Sift
Benign
1.0
T
Sift4G
Benign
0.91
T
Vest4
0.11
MutPred
0.20
Loss of catalytic residue at G8 (P = 0.0483);
MVP
0.55
MPC
0.46
ClinPred
0.057
T
GERP RS
-2.2
gMVP
0.36

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-955575; API