1-1054900-C-T

Variant names:

• chr1-1054900-C-T
• rs4275402
• NM_198576.4:c.6057C>T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_198576.4(AGRN):​c.6057C>T​(p.Asp2019Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.682 in 1,549,936 control chromosomes in the GnomAD database, including 367,096 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. DV2019D) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.59 (28846 hom., cov: 34)
  • Exomes 𝑓: 0.69 (338250 hom.)
• Consequence: AGRN NM_198576.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.712

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]

ENSG00000242590 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 1-1054900-C-T is Benign according to our data. Variant chr1-1054900-C-T is described in ClinVar as [Benign]. Clinvar id is 128319.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.712 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.791 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGRN	NM_198576.4	c.6057C>T	p.Asp2019Asp	synonymous_variant	Exon 36 of 36	ENST00000379370.7	NP_940978.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGRN	ENST00000379370.7	c.6057C>T	p.Asp2019Asp	synonymous_variant	Exon 36 of 36	1	NM_198576.4	ENSP00000368678.2

Frequencies

GnomAD3 genomes AF: 0.591 AC: 89880 AN: 152000 Hom.: 28830 Cov.: 34

Gnomad AFR AF: 0.323

Gnomad AMI AF: 0.673

Gnomad AMR AF: 0.720

Gnomad ASJ AF: 0.662

Gnomad EAS AF: 0.812

Gnomad SAS AF: 0.607

Gnomad FIN AF: 0.634

Gnomad MID AF: 0.639

Gnomad NFE AF: 0.696

Gnomad OTH AF: 0.600

GnomAD3 exomes AF: 0.676 AC: 104123 AN: 153932 Hom.: 36102 AF XY: 0.675 AC XY: 55454 AN XY: 82208

Gnomad AFR exome AF: 0.311

Gnomad AMR exome AF: 0.772

Gnomad ASJ exome AF: 0.658

Gnomad EAS exome AF: 0.814

Gnomad SAS exome AF: 0.613

Gnomad FIN exome AF: 0.641

Gnomad NFE exome AF: 0.698

Gnomad OTH exome AF: 0.676

GnomAD4 exome AF: 0.692 AC: 967055 AN: 1397818 Hom.: 338250 Cov.: 88 AF XY: 0.690 AC XY: 475706 AN XY: 689810

Gnomad4 AFR exome AF: 0.308

Gnomad4 AMR exome AF: 0.762

Gnomad4 ASJ exome AF: 0.658

Gnomad4 EAS exome AF: 0.830

Gnomad4 SAS exome AF: 0.612

Gnomad4 FIN exome AF: 0.645

Gnomad4 NFE exome AF: 0.706

Gnomad4 OTH exome AF: 0.669

GnomAD4 genome AF: 0.591 AC: 89927 AN: 152118 Hom.: 28846 Cov.: 34 AF XY: 0.592 AC XY: 44024 AN XY: 74384

Gnomad4 AFR AF: 0.323

Gnomad4 AMR AF: 0.720

Gnomad4 ASJ AF: 0.662

Gnomad4 EAS AF: 0.812

Gnomad4 SAS AF: 0.607

Gnomad4 FIN AF: 0.634

Gnomad4 NFE AF: 0.696

Gnomad4 OTH AF: 0.603

Alfa AF: 0.662 Hom.: 12282

Bravo AF: 0.588

Asia WGS AF: 0.693 AC: 2411 AN: 3478

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

- -

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. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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	-0.52
CADD	Benign	0.36
DANN	Benign	0.77
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.5

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

Publications

LitVar

Other links and lift over

dbSNP: rs4275402; hg19: chr1-990280; COSMIC: COSV65070964; COSMIC: COSV65070964;