1-1046551-A-G

Variant names:

• chr1-1046551-A-G
• rs2465128
• NM_198576.4:c.3066A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_198576.4(AGRN):​c.3066A>G​(p.Ser1022Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.892 in 1,610,386 control chromosomes in the GnomAD database, including 647,914 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.80 (51075 hom., cov: 30)
  • Exomes 𝑓: 0.90 (596839 hom.)
• Consequence: AGRN NM_198576.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.03
• Publications: 16 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BP6: Variant 1-1046551-A-G is Benign according to our data. Variant chr1-1046551-A-G is described in ClinVar as Benign. ClinVar VariationId is 128297.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.03 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.94 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198576.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGRN	NM_198576.4	MANE Select	c.3066A>G	p.Ser1022Ser	synonymous	Exon 18 of 36	NP_940978.2
	AGRN	NM_001305275.2		c.3066A>G	p.Ser1022Ser	synonymous	Exon 18 of 39	NP_001292204.1
	AGRN	NM_001364727.2		c.2751A>G	p.Ser917Ser	synonymous	Exon 17 of 36	NP_001351656.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGRN	ENST00000379370.7	TSL:1 MANE Select	c.3066A>G	p.Ser1022Ser	synonymous	Exon 18 of 36	ENSP00000368678.2
	AGRN	ENST00000651234.1		c.2751A>G	p.Ser917Ser	synonymous	Exon 17 of 38	ENSP00000499046.1
	AGRN	ENST00000652369.2		c.2751A>G	p.Ser917Ser	synonymous	Exon 17 of 35	ENSP00000498543.1

Frequencies

GnomAD3 genomes AF: 0.802 AC: 121546 AN: 151638 Hom.: 51078 Cov.: 30

Gnomad AFR AF: 0.514

Gnomad AMI AF: 0.986

Gnomad AMR AF: 0.881

Gnomad ASJ AF: 0.893

Gnomad EAS AF: 0.962

Gnomad SAS AF: 0.892

Gnomad FIN AF: 0.936

Gnomad MID AF: 0.851

Gnomad NFE AF: 0.910

Gnomad OTH AF: 0.824

GnomAD2 exomes AF: 0.887 AC: 216630 AN: 244354 AF XY: 0.891

Gnomad AFR exome AF: 0.497

Gnomad AMR exome AF: 0.930

Gnomad ASJ exome AF: 0.888

Gnomad EAS exome AF: 0.968

Gnomad FIN exome AF: 0.932

Gnomad NFE exome AF: 0.906

Gnomad OTH exome AF: 0.884

GnomAD4 exome AF: 0.902 AC: 1315696 AN: 1458630 Hom.: 596839 Cov.: 79 AF XY: 0.902 AC XY: 654709 AN XY: 725646

African (AFR) AF: 0.488 AC: 16341 AN: 33468

American (AMR) AF: 0.923 AC: 41210 AN: 44638

Ashkenazi Jewish (ASJ) AF: 0.886 AC: 23110 AN: 26098

East Asian (EAS) AF: 0.967 AC: 38383 AN: 39682

South Asian (SAS) AF: 0.887 AC: 76429 AN: 86206

European-Finnish (FIN) AF: 0.929 AC: 47205 AN: 50810

Middle Eastern (MID) AF: 0.822 AC: 4737 AN: 5766

European-Non Finnish (NFE) AF: 0.913 AC: 1015153 AN: 1111634

Other (OTH) AF: 0.881 AC: 53128 AN: 60328

GnomAD4 genome AF: 0.801 AC: 121566 AN: 151756 Hom.: 51075 Cov.: 30 AF XY: 0.805 AC XY: 59735 AN XY: 74236

African (AFR) AF: 0.513 AC: 21146 AN: 41212

American (AMR) AF: 0.881 AC: 13476 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.893 AC: 3091 AN: 3462

East Asian (EAS) AF: 0.962 AC: 4953 AN: 5148

South Asian (SAS) AF: 0.891 AC: 4287 AN: 4812

European-Finnish (FIN) AF: 0.936 AC: 9906 AN: 10582

Middle Eastern (MID) AF: 0.847 AC: 249 AN: 294

European-Non Finnish (NFE) AF: 0.910 AC: 61819 AN: 67938

Other (OTH) AF: 0.826 AC: 1742 AN: 2108

Alfa AF: 0.881 Hom.: 18957

Bravo AF: 0.783

Asia WGS AF: 0.903 AC: 3142 AN: 3478

EpiCase AF: 0.902

EpiControl AF: 0.897

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Aug 15, 2013

Genetic Services Laboratory, University of Chicago

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.12
DANN	Benign	0.19
PhyloP100		-1.0
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2465128; hg19: chr1-981931; COSMIC: COSV65068047; COSMIC: COSV65068047;