1-1051820-C-T

Variant names:

• chr1-1051820-C-T
• rs9803031
• NM_198576.4:c.5651+5C>T

Variant summary

Our verdict is Benign. The variant received -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 region, 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_region, intron
• Scores: Splicing: ADA: 0.0002423
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.17
• Publications: 13 publications found

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]

AGRN Gene-Disease associations (from GenCC):

• congenital myasthenic syndrome 8

  Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• presynaptic congenital myasthenic syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• postsynaptic congenital myasthenic syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 128317.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
AGRN	NM_198576.4	c.5651+5C>T		splice_region_variant, intron_variant	Intron 33 of 35	ENST00000379370.7	NP_940978.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGRN	ENST00000379370.7	c.5651+5C>T		splice_region_variant, intron_variant	Intron 33 of 35	1	NM_198576.4	ENSP00000368678.2

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

GnomAD2 exomes AF: 0.887 AC: 221888 AN: 250118 AF XY: 0.893

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 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

African (AFR) AF: 0.424 AC: 14197 AN: 33474

American (AMR) AF: 0.926 AC: 41381 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.889 AC: 23225 AN: 26126

East Asian (EAS) AF: 0.998 AC: 39608 AN: 39696

South Asian (SAS) AF: 0.883 AC: 76136 AN: 86252

European-Finnish (FIN) AF: 0.947 AC: 50101 AN: 52888

Middle Eastern (MID) AF: 0.832 AC: 4801 AN: 5768

European-Non Finnish (NFE) AF: 0.914 AC: 1015892 AN: 1111856

Other (OTH) AF: 0.882 AC: 53290 AN: 60386

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

African (AFR) AF: 0.452 AC: 18757 AN: 41510

American (AMR) AF: 0.886 AC: 13559 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.895 AC: 3108 AN: 3472

East Asian (EAS) AF: 0.995 AC: 5131 AN: 5158

South Asian (SAS) AF: 0.886 AC: 4270 AN: 4820

European-Finnish (FIN) AF: 0.955 AC: 10130 AN: 10612

Middle Eastern (MID) AF: 0.861 AC: 253 AN: 294

European-Non Finnish (NFE) AF: 0.911 AC: 61927 AN: 68000

Other (OTH) AF: 0.816 AC: 1724 AN: 2114

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

Aug 15, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 19, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Congenital myasthenic syndrome 8 Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.56
DANN	Benign	0.74
PhyloP100		-1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs9803031; hg19: chr1-987200;