chr1-1049450-GTG-CTA

Variant names:

• chr1-1049450-GTG-CTA
• NM_198576.4:c.4513_4514+1delGTGinsCTA
• AGRN p.Val1505Leu

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PVS1_Moderate

The NM_198576.4(AGRN):​c.4513_4514+1delGTGinsCTA​(p.Val1505Leu) variant causes a splice donor, missense, splice region, intron change. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1505M) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: AGRN NM_198576.4 splice_donor, missense, splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.23
• 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: 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.035190616 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.

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.4513_4514+1delGTGinsCTA	p.Val1505Leu	splice_donor missense splice_region intron	N/A	NP_940978.2
	AGRN	NM_001305275.2		c.4513_4514+1delGTGinsCTA	p.Val1505Leu	splice_donor missense splice_region intron	N/A	NP_001292204.1	O00468-1
	AGRN	NM_001364727.2		c.4198_4199+1delGTGinsCTA	p.Val1400Leu	splice_donor missense splice_region intron	N/A	NP_001351656.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGRN	ENST00000379370.7	TSL:1 MANE Select	c.4513_4514+1delGTGinsCTA	p.Val1505Leu	splice_donor missense splice_region intron	N/A	ENSP00000368678.2	O00468-6
	AGRN	ENST00000651234.1		c.4198_4199+1delGTGinsCTA	p.Val1400Leu	splice_donor missense splice_region intron	N/A	ENSP00000499046.1	A0A494C1I6
	AGRN	ENST00000652369.2		c.4198_4199+1delGTGinsCTA	p.Val1400Leu	splice_donor missense splice_region intron	N/A	ENSP00000498543.1	A0A494C0G5

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.2

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr1-984830;