Menu
GeneBe

rs376592885

chr1-1049569-G-A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM2BP4_StrongBP6_Very_StrongBP7

The NM_198576.4(AGRN):c.4518G>A(p.Ala1506=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000204 in 1,589,854 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00021 ( 1 hom. )

Consequence

AGRN
NM_198576.4 synonymous

Scores

2

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.343
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 Benign. Variant got -11 ACMG points.

PM2
?
    PM2 - Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
Very rare variant in population databases, with high coverage;
BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.55).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 1-1049569-G-A is Benign according to our data. Variant chr1-1049569-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 263187.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
?
    BP7 - A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
Synonymous conserved (PhyloP=0.343 with no splicing effect.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
AGRNNM_198576.4 linkuse as main transcriptc.4518G>A p.Ala1506= synonymous_variant 26/36 ENST00000379370.7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
AGRNENST00000379370.7 linkuse as main transcriptc.4518G>A p.Ala1506= synonymous_variant 26/361 NM_198576.4 P1O00468-6
AGRNENST00000651234.1 linkuse as main transcriptc.4203G>A p.Ala1401= synonymous_variant 25/38
AGRNENST00000652369.1 linkuse as main transcriptc.4203G>A p.Ala1401= synonymous_variant 25/35
AGRNENST00000620552.4 linkuse as main transcriptc.4104G>A p.Ala1368= synonymous_variant 26/395

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.000177
AC:
27
AN:
152202
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000193
Gnomad SAS
AF:
0.00124
Gnomad FIN
AF:
0.0000942
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000265
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000240
AC:
49
AN:
204082
Hom.:
0
AF XY:
0.000262
AC XY:
29
AN XY:
110674
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000204
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000660
Gnomad SAS exome
AF:
0.000408
Gnomad FIN exome
AF:
0.000176
Gnomad NFE exome
AF:
0.000213
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000207
AC:
297
AN:
1437534
Hom.:
1
Cov.:
44
AF XY:
0.000212
AC XY:
151
AN XY:
712976
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000198
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000311
Gnomad4 SAS exome
AF:
0.000444
Gnomad4 FIN exome
AF:
0.000262
Gnomad4 NFE exome
AF:
0.000199
Gnomad4 OTH exome
AF:
0.000118
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.000177
AC:
27
AN:
152320
Hom.:
0
Cov.:
32
AF XY:
0.000269
AC XY:
20
AN XY:
74476
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.00124
Gnomad4 FIN
AF:
0.0000942
Gnomad4 NFE
AF:
0.000265
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000423
Hom.:
0
Bravo
AF:
0.000140

ClinVar

Significance: Likely benign
Submissions summary: Benign:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:1
Likely benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
Congenital myasthenic syndrome 8 Benign:1
Likely benign, criteria provided, single submitterclinical testingInvitaeNov 27, 2021- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.55
Cadd
Benign
7.1
Dann
Benign
0.51
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.8

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

LitVar

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

Other links and lift over

dbSNP: rs376592885; hg19: chr1-984949; API