NM_198576.4:c.5223C>T

Variant names:

• chr1-1050807-C-T
• rs147681220
• NM_198576.4:c.5223C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_198576.4(AGRN):​c.5223C>T​(p.Gly1741Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00556 in 1,592,094 control chromosomes in the GnomAD database, including 112 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0077 (25 hom., cov: 33)
  • Exomes 𝑓: 0.0053 (87 hom.)
• Consequence: AGRN NM_198576.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.25
• Publications: 0 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=-0.67).
• BP6: Variant 1-1050807-C-T is Benign according to our data. Variant chr1-1050807-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 474144.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.25 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00774 (1178/152182) while in subpopulation NFE AF = 0.00546 (371/67974). AF 95% confidence interval is 0.005. There are 25 homozygotes in GnomAd4. There are 761 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 25 AR,AD gene

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.5223C>T	p.Gly1741Gly	synonymous	Exon 30 of 36	NP_940978.2
	AGRN	NM_001305275.2		c.5223C>T	p.Gly1741Gly	synonymous	Exon 30 of 39	NP_001292204.1
	AGRN	NM_001364727.2		c.4908C>T	p.Gly1636Gly	synonymous	Exon 29 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.5223C>T	p.Gly1741Gly	synonymous	Exon 30 of 36	ENSP00000368678.2
	AGRN	ENST00000651234.1		c.4908C>T	p.Gly1636Gly	synonymous	Exon 29 of 38	ENSP00000499046.1
	AGRN	ENST00000652369.2		c.4908C>T	p.Gly1636Gly	synonymous	Exon 29 of 35	ENSP00000498543.1

Frequencies

GnomAD3 genomes AF: 0.00775 AC: 1178 AN: 152064 Hom.: 25 Cov.: 33

Gnomad AFR AF: 0.000676

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00309

Gnomad SAS AF: 0.00477

Gnomad FIN AF: 0.0647

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00546

Gnomad OTH AF: 0.00383

GnomAD2 exomes AF: 0.00793 AC: 1680 AN: 211816 AF XY: 0.00775

Gnomad AFR exome AF: 0.000534

Gnomad AMR exome AF: 0.00486

Gnomad ASJ exome AF: 0.000323

Gnomad EAS exome AF: 0.000489

Gnomad FIN exome AF: 0.0552

Gnomad NFE exome AF: 0.00592

Gnomad OTH exome AF: 0.0100

GnomAD4 exome AF: 0.00533 AC: 7681 AN: 1439912 Hom.: 87 Cov.: 34 AF XY: 0.00535 AC XY: 3827 AN XY: 715272

African (AFR) AF: 0.000511 AC: 17 AN: 33238

American (AMR) AF: 0.00501 AC: 213 AN: 42490

Ashkenazi Jewish (ASJ) AF: 0.000816 AC: 21 AN: 25750

East Asian (EAS) AF: 0.000308 AC: 12 AN: 39024

South Asian (SAS) AF: 0.00481 AC: 404 AN: 83988

European-Finnish (FIN) AF: 0.0522 AC: 2390 AN: 45822

Middle Eastern (MID) AF: 0.00366 AC: 16 AN: 4366

European-Non Finnish (NFE) AF: 0.00389 AC: 4301 AN: 1105654

Other (OTH) AF: 0.00515 AC: 307 AN: 59580

GnomAD4 genome AF: 0.00774 AC: 1178 AN: 152182 Hom.: 25 Cov.: 33 AF XY: 0.0102 AC XY: 761 AN XY: 74376

African (AFR) AF: 0.000674 AC: 28 AN: 41516

American (AMR) AF: 0.00262 AC: 40 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3472

East Asian (EAS) AF: 0.00310 AC: 16 AN: 5164

South Asian (SAS) AF: 0.00477 AC: 23 AN: 4822

European-Finnish (FIN) AF: 0.0647 AC: 687 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00546 AC: 371 AN: 67974

Other (OTH) AF: 0.00379 AC: 8 AN: 2112

Alfa AF: 0.00602 Hom.: 3

Bravo AF: 0.00272

Asia WGS AF: 0.00635 AC: 22 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Sep 02, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Sep 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

AGRN: BP4, BP7, BS2

AGRN-related disorder Benign:1

May 02, 2024

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Congenital myasthenic syndrome 8 Benign:1

Jan 31, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	0.27
DANN	Benign	0.74
PhyloP100		-1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs147681220; hg19: chr1-986187; COSMIC: COSV101038847; COSMIC: COSV101038847;