1-1045523-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_198576.4(AGRN):​c.2536C>T​(p.Pro846Ser) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000501 in 1,612,576 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. P846P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00028 ( 0 hom., cov: 34)
Exomes 𝑓: 0.00052 ( 0 hom. )

Consequence

AGRN
NM_198576.4 missense, splice_region

Scores

4
10
3
Splicing: ADA: 0.9908
1
1

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 7.36
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 Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.759

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
AGRNNM_198576.4 linkc.2536C>T p.Pro846Ser missense_variant, splice_region_variant 14/36 ENST00000379370.7 NP_940978.2 O00468-6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
AGRNENST00000379370.7 linkc.2536C>T p.Pro846Ser missense_variant, splice_region_variant 14/361 NM_198576.4 ENSP00000368678.2 O00468-6

Frequencies

GnomAD3 genomes
AF:
0.000276
AC:
42
AN:
152242
Hom.:
0
Cov.:
34
show subpopulations
Gnomad AFR
AF:
0.0000724
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000558
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000221
AC:
55
AN:
248868
Hom.:
0
AF XY:
0.000229
AC XY:
31
AN XY:
135208
show subpopulations
Gnomad AFR exome
AF:
0.0000624
Gnomad AMR exome
AF:
0.0000579
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000446
Gnomad OTH exome
AF:
0.000329
GnomAD4 exome
AF:
0.000525
AC:
766
AN:
1460334
Hom.:
0
Cov.:
34
AF XY:
0.000529
AC XY:
384
AN XY:
726470
show subpopulations
Gnomad4 AFR exome
AF:
0.0000896
Gnomad4 AMR exome
AF:
0.0000447
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000232
Gnomad4 FIN exome
AF:
0.0000192
Gnomad4 NFE exome
AF:
0.000668
Gnomad4 OTH exome
AF:
0.000232
GnomAD4 genome
AF:
0.000276
AC:
42
AN:
152242
Hom.:
0
Cov.:
34
AF XY:
0.000255
AC XY:
19
AN XY:
74384
show subpopulations
Gnomad4 AFR
AF:
0.0000724
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000558
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000599
Hom.:
0
Bravo
AF:
0.000340
TwinsUK
AF:
0.000539
AC:
2
ALSPAC
AF:
0.000519
AC:
2
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000349
AC:
3
ExAC
AF:
0.000124
AC:
15
EpiCase
AF:
0.000491
EpiControl
AF:
0.000356

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxJul 24, 2019In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge -
Congenital myasthenic syndrome 8 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpAug 16, 2022This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 846 of the AGRN protein (p.Pro846Ser). This variant is present in population databases (rs138248828, gnomAD 0.05%). 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: 572779). 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"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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
-0.090
T
BayesDel_noAF
Uncertain
-0.030
CADD
Pathogenic
26
DANN
Uncertain
1.0
Eigen
Uncertain
0.52
Eigen_PC
Uncertain
0.49
FATHMM_MKL
Uncertain
0.90
D
LIST_S2
Uncertain
0.94
D;D
M_CAP
Pathogenic
0.36
D
MetaRNN
Pathogenic
0.76
D;D
MetaSVM
Uncertain
0.20
D
MutationAssessor
Benign
1.6
L;.
PrimateAI
Uncertain
0.49
T
PROVEAN
Pathogenic
-6.0
D;.
REVEL
Uncertain
0.41
Sift
Pathogenic
0.0
D;.
Sift4G
Uncertain
0.0030
D;D
Vest4
0.63
MVP
0.87
MPC
0.38
ClinPred
0.35
T
GERP RS
5.4
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
gMVP
0.20

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
0.99
dbscSNV1_RF
Benign
0.72
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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs138248828; hg19: chr1-980903; API