1-1051820-C-T

Position:

• chr1-1051820-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_198576.4(AGRN):​c.5651+5C>T variant causes a splice donor 5th base, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.892 in 1,613,352 control chromosomes in the GnomAD database, including 650,064 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.79 (50443 hom., cov: 34)
  • Exomes 𝑓: 0.90 (599621 hom.)
• Consequence: AGRN NM_198576.4 splice_donor_5th_base, intron
• Scores: Splicing: ADA: 0.0002423
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.17

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 1-1051820-C-T is Benign according to our data. Variant chr1-1051820-C-T is described in ClinVar as [Benign]. Clinvar id is 128317.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-1051820-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.972 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AGRN	NM_198576.4	c.5651+5C>T		splice_donor_5th_base_variant, intron_variant		ENST00000379370.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AGRN	ENST00000379370.7	c.5651+5C>T		splice_donor_5th_base_variant, intron_variant		1	NM_198576.4	P1
AGRN	ENST00000620552.4	c.5249+5C>T		splice_donor_5th_base_variant, intron_variant		5
AGRN	ENST00000651234.1	c.5348+5C>T		splice_donor_5th_base_variant, intron_variant
AGRN	ENST00000652369.1	c.5336+5C>T		splice_donor_5th_base_variant, intron_variant

Frequencies

GnomAD3 genomes AF: 0.787 AC: 119733 AN: 152082 Hom.: 50443 Cov.: 34

Gnomad AFR AF: 0.453

Gnomad AMI AF: 0.986

Gnomad AMR AF: 0.886

Gnomad ASJ AF: 0.895

Gnomad EAS AF: 0.995

Gnomad SAS AF: 0.887

Gnomad FIN AF: 0.955

Gnomad MID AF: 0.864

Gnomad NFE AF: 0.911

Gnomad OTH AF: 0.813

GnomAD3 exomes AF: 0.887 AC: 221888 AN: 250118 Hom.: 100369 AF XY: 0.893 AC XY: 121065 AN XY: 135608

Gnomad AFR exome AF: 0.439

Gnomad AMR exome AF: 0.932

Gnomad ASJ exome AF: 0.892

Gnomad EAS exome AF: 0.996

Gnomad SAS exome AF: 0.883

Gnomad FIN exome AF: 0.950

Gnomad NFE exome AF: 0.908

Gnomad OTH exome AF: 0.893

GnomAD4 exome AF: 0.902 AC: 1318631 AN: 1461152 Hom.: 599621 Cov.: 60 AF XY: 0.903 AC XY: 656161 AN XY: 726882

Gnomad4 AFR exome AF: 0.424

Gnomad4 AMR exome AF: 0.926

Gnomad4 ASJ exome AF: 0.889

Gnomad4 EAS exome AF: 0.998

Gnomad4 SAS exome AF: 0.883

Gnomad4 FIN exome AF: 0.947

Gnomad4 NFE exome AF: 0.914

Gnomad4 OTH exome AF: 0.882

GnomAD4 genome AF: 0.787 AC: 119758 AN: 152200 Hom.: 50443 Cov.: 34 AF XY: 0.793 AC XY: 59011 AN XY: 74408

Gnomad4 AFR AF: 0.452

Gnomad4 AMR AF: 0.886

Gnomad4 ASJ AF: 0.895

Gnomad4 EAS AF: 0.995

Gnomad4 SAS AF: 0.886

Gnomad4 FIN AF: 0.955

Gnomad4 NFE AF: 0.911

Gnomad4 OTH AF: 0.816

Alfa AF: 0.857 Hom.: 32550

Bravo AF: 0.767

Asia WGS AF: 0.913 AC: 3175 AN: 3478

EpiCase AF: 0.904

EpiControl AF: 0.898

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 19, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Congenital myasthenic syndrome 8 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.56
DANN	Benign	0.74
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00024
dbscSNV1_RF	Benign	0.016
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

Other links and lift over

dbSNP: rs9803031; hg19: chr1-987200;