rs113020870

Positions:

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_198576.4(AGRN):​c.4839C>T​(p.Cys1613Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00422 in 1,513,062 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0030 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0044 ( 21 hom. )

Consequence

AGRN
NM_198576.4 synonymous

Scores

2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.325
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 -16 ACMG points.

BP6
Variant 1-1049997-C-T is Benign according to our data. Variant chr1-1049997-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 263189.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00296 (429/144898) while in subpopulation NFE AF= 0.00435 (288/66144). AF 95% confidence interval is 0.00394. There are 0 homozygotes in gnomad4. There are 212 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High Homozygotes in GnomAdExome4 at 21 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
AGRNNM_198576.4 linkc.4839C>T p.Cys1613Cys synonymous_variant 27/36 ENST00000379370.7 NP_940978.2 O00468-6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
AGRNENST00000379370.7 linkc.4839C>T p.Cys1613Cys synonymous_variant 27/361 NM_198576.4 ENSP00000368678.2 O00468-6
AGRNENST00000651234.1 linkc.4524C>T p.Cys1508Cys synonymous_variant 26/38 ENSP00000499046.1 A0A494C1I6
AGRNENST00000652369.1 linkc.4524C>T p.Cys1508Cys synonymous_variant 26/35 ENSP00000498543.1 A0A494C0G5
AGRNENST00000620552.4 linkc.4425C>T p.Cys1475Cys synonymous_variant 27/395 ENSP00000484607.1 A0A087X208

Frequencies

GnomAD3 genomes
AF:
0.00296
AC:
429
AN:
144784
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000995
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00373
Gnomad ASJ
AF:
0.000592
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000479
Gnomad FIN
AF:
0.00391
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00435
Gnomad OTH
AF:
0.00294
GnomAD3 exomes
AF:
0.00273
AC:
647
AN:
237116
Hom.:
2
AF XY:
0.00268
AC XY:
350
AN XY:
130706
show subpopulations
Gnomad AFR exome
AF:
0.000974
Gnomad AMR exome
AF:
0.00129
Gnomad ASJ exome
AF:
0.000415
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000430
Gnomad FIN exome
AF:
0.00541
Gnomad NFE exome
AF:
0.00427
Gnomad OTH exome
AF:
0.00223
GnomAD4 exome
AF:
0.00436
AC:
5961
AN:
1368164
Hom.:
21
Cov.:
72
AF XY:
0.00420
AC XY:
2856
AN XY:
680044
show subpopulations
Gnomad4 AFR exome
AF:
0.000700
Gnomad4 AMR exome
AF:
0.00155
Gnomad4 ASJ exome
AF:
0.000442
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000539
Gnomad4 FIN exome
AF:
0.00485
Gnomad4 NFE exome
AF:
0.00517
Gnomad4 OTH exome
AF:
0.00288
GnomAD4 genome
AF:
0.00296
AC:
429
AN:
144898
Hom.:
0
Cov.:
33
AF XY:
0.00300
AC XY:
212
AN XY:
70584
show subpopulations
Gnomad4 AFR
AF:
0.000993
Gnomad4 AMR
AF:
0.00372
Gnomad4 ASJ
AF:
0.000592
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000478
Gnomad4 FIN
AF:
0.00391
Gnomad4 NFE
AF:
0.00435
Gnomad4 OTH
AF:
0.00291
Alfa
AF:
0.00349
Hom.:
1
Bravo
AF:
0.00258
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.00463
EpiControl
AF:
0.00339

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:3
Benign, criteria provided, single submitterclinical testingGeneDxOct 09, 2020- -
Benign, criteria provided, single submitterclinical testingAthena DiagnosticsDec 27, 2018- -
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenApr 01, 2024AGRN: PP3, BS2 -
not specified Benign:1
Likely benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
Congenital myasthenic syndrome 8 Benign:1
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 22, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.52
CADD
Benign
19
DANN
Benign
0.44
RBP_binding_hub_radar
0.97
RBP_regulation_power_radar
2.5

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.98
Details are displayed if max score is > 0.2
DS_DG_spliceai
0.98
Position offset: -2
DS_DL_spliceai
0.60
Position offset: 40

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: rs113020870; hg19: chr1-985377; COSMIC: COSV65067910; COSMIC: COSV65067910; API