1-1054900-C-T

Variant names:

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

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.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 (★★).

• 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
• Publications: 18 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: DEFINITIVE, STRONG Submitted by: ClinGen, 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

ENSG00000242590 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGRN	NM_198576.4	MANE Select	c.6057C>T	p.Asp2019Asp	synonymous	Exon 36 of 36	NP_940978.2
	AGRN	NM_001305275.2		c.6126C>T	p.Asp2042Asp	synonymous	Exon 39 of 39	NP_001292204.1	O00468-1
	AGRN	NM_001364727.2		c.5754C>T	p.Asp1918Asp	synonymous	Exon 36 of 36	NP_001351656.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGRN	ENST00000379370.7	TSL:1 MANE Select	c.6057C>T	p.Asp2019Asp	synonymous	Exon 36 of 36	ENSP00000368678.2	O00468-6
	AGRN	ENST00000461111.1	TSL:1	n.2173C>T		non_coding_transcript_exon	Exon 3 of 3
	AGRN	ENST00000651234.1		c.5811C>T	p.Asp1937Asp	synonymous	Exon 38 of 38	ENSP00000499046.1	A0A494C1I6

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

GnomAD2 exomes AF: 0.676 AC: 104123 AN: 153932 AF XY: 0.675

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 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

African (AFR) AF: 0.308 AC: 9780 AN: 31770

American (AMR) AF: 0.762 AC: 27531 AN: 36128

Ashkenazi Jewish (ASJ) AF: 0.658 AC: 16565 AN: 25172

East Asian (EAS) AF: 0.830 AC: 29822 AN: 35928

South Asian (SAS) AF: 0.612 AC: 48541 AN: 79286

European-Finnish (FIN) AF: 0.645 AC: 30503 AN: 47274

Middle Eastern (MID) AF: 0.661 AC: 2851 AN: 4316

European-Non Finnish (NFE) AF: 0.706 AC: 762723 AN: 1080050

Other (OTH) AF: 0.669 AC: 38739 AN: 57894

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

African (AFR) AF: 0.323 AC: 13380 AN: 41474

American (AMR) AF: 0.720 AC: 11016 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.662 AC: 2299 AN: 3472

East Asian (EAS) AF: 0.812 AC: 4207 AN: 5182

South Asian (SAS) AF: 0.607 AC: 2928 AN: 4820

European-Finnish (FIN) AF: 0.634 AC: 6727 AN: 10606

Middle Eastern (MID) AF: 0.646 AC: 190 AN: 294

European-Non Finnish (NFE) AF: 0.696 AC: 47297 AN: 67952

Other (OTH) AF: 0.603 AC: 1273 AN: 2112

Alfa AF: 0.658 Hom.: 12328

Bravo AF: 0.588

Asia WGS AF: 0.693 AC: 2411 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Congenital myasthenic syndrome 8 (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	0.36
DANN	Benign	0.77
PhyloP100		-0.71
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.5
Mutation Taster		=92/8	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: rs4275402; hg19: chr1-990280; COSMIC: COSV65070964; COSMIC: COSV65070964;