1-1048892-C-T

Variant names:

• chr1-1048892-C-T
• rs368555478
• NM_198576.4:c.4131C>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.4131C>T​(p.Phe1377Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00051 in 1,545,438 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0025 (0 hom., cov: 27)
  • Exomes 𝑓: 0.00029 (2 hom.)
• Consequence: AGRN NM_198576.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -2.59
• 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=-0.48).
• BP6: Variant 1-1048892-C-T is Benign according to our data. Variant chr1-1048892-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 392687.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.59 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00254 (386/151844) while in subpopulation AFR AF = 0.00856 (354/41352). AF 95% confidence interval is 0.00783. There are 0 homozygotes in GnomAd4. There are 177 alleles in the male GnomAd4 subpopulation. Median coverage is 27. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 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.4131C>T	p.Phe1377Phe	synonymous	Exon 24 of 36	NP_940978.2
	AGRN	NM_001305275.2		c.4131C>T	p.Phe1377Phe	synonymous	Exon 24 of 39	NP_001292204.1
	AGRN	NM_001364727.2		c.3816C>T	p.Phe1272Phe	synonymous	Exon 23 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.4131C>T	p.Phe1377Phe	synonymous	Exon 24 of 36	ENSP00000368678.2
	AGRN	ENST00000651234.1		c.3816C>T	p.Phe1272Phe	synonymous	Exon 23 of 38	ENSP00000499046.1
	AGRN	ENST00000652369.2		c.3816C>T	p.Phe1272Phe	synonymous	Exon 23 of 35	ENSP00000498543.1

Frequencies

GnomAD3 genomes AF: 0.00254 AC: 386 AN: 151730 Hom.: 0 Cov.: 27

Gnomad AFR AF: 0.00859

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000918

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00240

GnomAD2 exomes AF: 0.000566 AC: 89 AN: 157272 AF XY: 0.000494

Gnomad AFR exome AF: 0.00788

Gnomad AMR exome AF: 0.000537

Gnomad ASJ exome AF: 0.000119

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000113

Gnomad OTH exome AF: 0.000687

GnomAD4 exome AF: 0.000288 AC: 402 AN: 1393594 Hom.: 2 Cov.: 33 AF XY: 0.000249 AC XY: 171 AN XY: 686286

African (AFR) AF: 0.00862 AC: 273 AN: 31682

American (AMR) AF: 0.000621 AC: 23 AN: 37018

Ashkenazi Jewish (ASJ) AF: 0.0000398 AC: 1 AN: 25132

East Asian (EAS) AF: 0.0000276 AC: 1 AN: 36216

South Asian (SAS) AF: 0.0000252 AC: 2 AN: 79444

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45140

Middle Eastern (MID) AF: 0.000691 AC: 3 AN: 4342

European-Non Finnish (NFE) AF: 0.0000520 AC: 56 AN: 1077048

Other (OTH) AF: 0.000747 AC: 43 AN: 57572

GnomAD4 genome AF: 0.00254 AC: 386 AN: 151844 Hom.: 0 Cov.: 27 AF XY: 0.00238 AC XY: 177 AN XY: 74232

African (AFR) AF: 0.00856 AC: 354 AN: 41352

American (AMR) AF: 0.000917 AC: 14 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5138

South Asian (SAS) AF: 0.00 AC: 0 AN: 4808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10572

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 67916

Other (OTH) AF: 0.00237 AC: 5 AN: 2108

Alfa AF: 0.000157 Hom.: 0

Bravo AF: 0.00290

Asia WGS AF: 0.000577 AC: 2 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

Mar 27, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

AGRN: BP4, BP7

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

not specified Benign:1

Jan 10, 2017

GeneDx

Significance: Likely 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:1

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely 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	-0.48
CADD	Benign	0.25
DANN	Benign	0.58
PhyloP100		-2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs368555478; hg19: chr1-984272;