1-1050063-AGGGGGG-AGGG

Variant names:

• chr1-1050063-AGGG-A
• rs71576592
• NM_198576.4:c.4879+39_4879+41delGGG

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_198576.4(AGRN):​c.4879+39_4879+41delGGG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000258 in 1,027,260 control chromosomes in the GnomAD database, including 2 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00028 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00026 (2 hom.)
• 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: Likely_benign. The variant received -4 ACMG points.

• BS2: High Homozygotes in GnomAdExome4 at 2 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+39_4879+41delGGG		intron	N/A	NP_940978.2
	AGRN	NM_001305275.2		c.4879+39_4879+41delGGG		intron	N/A	NP_001292204.1	O00468-1
	AGRN	NM_001364727.2		c.4564+39_4564+41delGGG		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+29delGGG		intron	N/A	ENSP00000368678.2	O00468-6
	AGRN	ENST00000651234.1		c.4564+27_4564+29delGGG		intron	N/A	ENSP00000499046.1	A0A494C1I6
	AGRN	ENST00000652369.2		c.4564+27_4564+29delGGG		intron	N/A	ENSP00000498543.1	A0A494C0G5

Frequencies

GnomAD3 genomes AF: 0.000277 AC: 37 AN: 133790 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000948

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000707

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: 0.0000166

Gnomad OTH AF: 0.000529

GnomAD2 exomes AF: 0.000689 AC: 83 AN: 120388 AF XY: 0.000566

Gnomad AFR exome AF: 0.0103

Gnomad AMR exome AF: 0.000772

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000406

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000453

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000255 AC: 228 AN: 893382 Hom.: 2 AF XY: 0.000212 AC XY: 96 AN XY: 452002

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

African (AFR) AF: 0.00642 AC: 143 AN: 22276

American (AMR) AF: 0.000670 AC: 21 AN: 31354

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

East Asian (EAS) AF: 0.0000944 AC: 3 AN: 31778

South Asian (SAS) AF: 0.0000300 AC: 2 AN: 66648

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2862

European-Non Finnish (NFE) AF: 0.0000502 AC: 32 AN: 637880

Other (OTH) AF: 0.000673 AC: 27 AN: 40146

⚠️ 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 AF: 0.000276 AC: 37 AN: 133878 Hom.: 0 Cov.: 0 AF XY: 0.000183 AC XY: 12 AN XY: 65468

African (AFR) AF: 0.000945 AC: 34 AN: 35982

American (AMR) AF: 0.0000706 AC: 1 AN: 14162

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 4420

South Asian (SAS) AF: 0.00 AC: 0 AN: 4080

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9022

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

European-Non Finnish (NFE) AF: 0.0000166 AC: 1 AN: 60082

Other (OTH) AF: 0.000523 AC: 1 AN: 1912

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

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;