chr1-1050063-AGGGGG-A

Variant names:

• chr1-1050063-AGGGGG-A
• rs71576592
• NM_198576.4:c.4879+37_4879+41delGGGGG

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_198576.4(AGRN):​c.4879+37_4879+41delGGGGG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000224 in 894,164 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 0)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: AGRN NM_198576.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0630
• Publications: 1 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.

• PM2: Very rare variant in population databases, with high coverage

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.4879+37_4879+41delGGGGG		intron	N/A	NP_940978.2
	AGRN	NM_001305275.2		c.4879+37_4879+41delGGGGG		intron	N/A	NP_001292204.1	O00468-1
	AGRN	NM_001364727.2		c.4564+37_4564+41delGGGGG		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.4879+27_4879+31delGGGGG		intron	N/A	ENSP00000368678.2	O00468-6
	AGRN	ENST00000651234.1		c.4564+27_4564+31delGGGGG		intron	N/A	ENSP00000499046.1	A0A494C1I6
	AGRN	ENST00000652369.2		c.4564+27_4564+31delGGGGG		intron	N/A	ENSP00000498543.1	A0A494C0G5

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome AF: 0.00000224 AC: 2 AN: 894164 Hom.: 0 AF XY: 0.00000442 AC XY: 2 AN XY: 452324

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000881 AC: 2 AN: 22694

American (AMR) AF: 0.00 AC: 0 AN: 31442

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19610

East Asian (EAS) AF: 0.00 AC: 0 AN: 31798

South Asian (SAS) AF: 0.00 AC: 0 AN: 66678

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40828

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2876

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 638018

Other (OTH) AF: 0.00 AC: 0 AN: 40220

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.063

Splicing

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

Other links and lift over

dbSNP: rs71576592; hg19: chr1-985443;