chr1-1050063-AGG-A

Variant names:

• chr1-1050063-AGG-A
• rs71576592
• NM_198576.4:c.4879+40_4879+41delGG

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_198576.4(AGRN):​c.4879+40_4879+41delGG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00187 in 892,988 control chromosomes in the GnomAD database, including 38 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.013 (38 hom., cov: 0)
  • Exomes 𝑓: 0.0019 (38 hom.)
  • Failed GnomAD Quality Control
• Consequence: AGRN NM_198576.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0280
• 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: Benign. The variant received -8 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. GnomAdExome4 allele frequency = 0.00187 (1667/892988) while in subpopulation AFR AF = 0.04 (892/22286). AF 95% confidence interval is 0.0378. There are 38 homozygotes in GnomAdExome4. There are 747 alleles in the male GnomAdExome4 subpopulation. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 38 AR,AD gene

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+40_4879+41delGG		intron	N/A	NP_940978.2
	AGRN	NM_001305275.2		c.4879+40_4879+41delGG		intron	N/A	NP_001292204.1	O00468-1
	AGRN	NM_001364727.2		c.4564+40_4564+41delGG		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+28delGG		intron	N/A	ENSP00000368678.2	O00468-6
	AGRN	ENST00000651234.1		c.4564+27_4564+28delGG		intron	N/A	ENSP00000499046.1	A0A494C1I6
	AGRN	ENST00000652369.2		c.4564+27_4564+28delGG		intron	N/A	ENSP00000498543.1	A0A494C0G5

Frequencies

GnomAD3 genomes AF: 0.0126 AC: 1686 AN: 133596 Hom.: 38 Cov.: 0

Gnomad AFR AF: 0.0435

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00524

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00271

Gnomad SAS AF: 0.000490

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000449

Gnomad OTH AF: 0.00900

GnomAD2 exomes AF: 0.00278 AC: 335 AN: 120388 AF XY: 0.00228

Gnomad AFR exome AF: 0.0398

Gnomad AMR exome AF: 0.00275

Gnomad ASJ exome AF: 0.000313

Gnomad EAS exome AF: 0.000508

Gnomad FIN exome AF: 0.000257

Gnomad NFE exome AF: 0.000567

Gnomad OTH exome AF: 0.00203

GnomAD4 exome AF: 0.00187 AC: 1667 AN: 892988 Hom.: 38 AF XY: 0.00165 AC XY: 747 AN XY: 451752

African (AFR) AF: 0.0400 AC: 892 AN: 22286

American (AMR) AF: 0.00323 AC: 101 AN: 31296

Ashkenazi Jewish (ASJ) AF: 0.000204 AC: 4 AN: 19606

East Asian (EAS) AF: 0.000189 AC: 6 AN: 31778

South Asian (SAS) AF: 0.000495 AC: 33 AN: 66634

European-Finnish (FIN) AF: 0.000122 AC: 5 AN: 40818

Middle Eastern (MID) AF: 0.00421 AC: 12 AN: 2852

European-Non Finnish (NFE) AF: 0.000717 AC: 457 AN: 637610

Other (OTH) AF: 0.00391 AC: 157 AN: 40108

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0126 AC: 1688 AN: 133680 Hom.: 38 Cov.: 0 AF XY: 0.0126 AC XY: 822 AN XY: 65368

African (AFR) AF: 0.0435 AC: 1558 AN: 35822

American (AMR) AF: 0.00516 AC: 73 AN: 14140

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3158

East Asian (EAS) AF: 0.00249 AC: 11 AN: 4414

South Asian (SAS) AF: 0.000490 AC: 2 AN: 4080

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9020

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 282

European-Non Finnish (NFE) AF: 0.000449 AC: 27 AN: 60076

Other (OTH) AF: 0.00890 AC: 17 AN: 1910

Alfa AF: 0.00 Hom.: 425

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.028
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: rs71576592; hg19: chr1-985443;