rs1181560428

Variant names:

• chr1-1048986-C-T
• rs1181560428
• NM_198576.4:c.4225C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Moderate BP6_Moderate BP7

The ENST00000379370.7(AGRN):​c.4225C>T​(p.Leu1409Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000012 in 1,579,598 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. L1409L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 26)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: AGRN ENST00000379370.7 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.85
• 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 1-1048986-C-T is Benign according to our data. Variant chr1-1048986-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 541182.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=2.85 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000379370.7. 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.4225C>T	p.Leu1409Leu	synonymous	Exon 24 of 36	NP_940978.2
	AGRN	NM_001305275.2		c.4225C>T	p.Leu1409Leu	synonymous	Exon 24 of 39	NP_001292204.1
	AGRN	NM_001364727.2		c.3910C>T	p.Leu1304Leu	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.4225C>T	p.Leu1409Leu	synonymous	Exon 24 of 36	ENSP00000368678.2
	AGRN	ENST00000651234.1		c.3910C>T	p.Leu1304Leu	synonymous	Exon 23 of 38	ENSP00000499046.1
	AGRN	ENST00000652369.2		c.3910C>T	p.Leu1304Leu	synonymous	Exon 23 of 35	ENSP00000498543.1

Frequencies

GnomAD3 genomes AF: 0.00000661 AC: 1 AN: 151202 Hom.: 0 Cov.: 26

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000126 AC: 18 AN: 1428396 Hom.: 0 Cov.: 51 AF XY: 0.0000155 AC XY: 11 AN XY: 707706

African (AFR) AF: 0.00 AC: 0 AN: 32774

American (AMR) AF: 0.00 AC: 0 AN: 40702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25522

East Asian (EAS) AF: 0.00 AC: 0 AN: 38066

South Asian (SAS) AF: 0.00 AC: 0 AN: 81608

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49552

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4156

European-Non Finnish (NFE) AF: 0.0000164 AC: 18 AN: 1097008

Other (OTH) AF: 0.00 AC: 0 AN: 59008

GnomAD4 genome AF: 0.00000661 AC: 1 AN: 151202 Hom.: 0 Cov.: 26 AF XY: 0.00 AC XY: 0 AN XY: 73832

African (AFR) AF: 0.00 AC: 0 AN: 40970

American (AMR) AF: 0.00 AC: 0 AN: 15192

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5126

South Asian (SAS) AF: 0.00 AC: 0 AN: 4790

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10530

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67830

Other (OTH) AF: 0.00 AC: 0 AN: 2074

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Congenital myasthenic syndrome 8 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	9.5
DANN	Benign	0.78
PhyloP100		2.9
Mutation Taster		=100/0	polymorphism

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: rs1181560428; hg19: chr1-984366;