1-1049065-C-T

Variant names:

• chr1-1049065-C-T
• rs199977575
• NM_198576.4:c.4298+6C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_001305275.2(AGRN):​c.4298+6C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000867 in 1,049,670 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000061 (0 hom., cov: 24)
  • Exomes 𝑓: 0.000090 (0 hom.)
• Consequence: AGRN NM_001305275.2 splice_region, intron
• Scores: Splicing: ADA: 0.00002191
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.63
• 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 1-1049065-C-T is Benign according to our data. Variant chr1-1049065-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 474131.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001305275.2. 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.4298+6C>T		splice_region intron	N/A	NP_940978.2
	AGRN	NM_001305275.2		c.4298+6C>T		splice_region intron	N/A	NP_001292204.1
	AGRN	NM_001364727.2		c.3983+6C>T		splice_region intron	N/A	NP_001351656.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGRN	ENST00000379370.7	TSL:1 MANE Select	c.4298+6C>T		splice_region intron	N/A	ENSP00000368678.2
	AGRN	ENST00000651234.1		c.3983+6C>T		splice_region intron	N/A	ENSP00000499046.1
	AGRN	ENST00000652369.2		c.3983+6C>T		splice_region intron	N/A	ENSP00000498543.1

Frequencies

GnomAD3 genomes AF: 0.0000612 AC: 8 AN: 130720 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.000123

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000221

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000478

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000104 AC: 12 AN: 115738 AF XY: 0.0000936

Gnomad AFR exome AF: 0.000966

Gnomad AMR exome AF: 0.000105

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000123

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000694

Gnomad OTH exome AF: 0.000295

GnomAD4 exome AF: 0.0000903 AC: 83 AN: 918870 Hom.: 0 Cov.: 39 AF XY: 0.0000902 AC XY: 42 AN XY: 465564

African (AFR) AF: 0.00159 AC: 29 AN: 18236

American (AMR) AF: 0.0000908 AC: 3 AN: 33040

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19668

East Asian (EAS) AF: 0.0000667 AC: 2 AN: 29964

South Asian (SAS) AF: 0.0000291 AC: 2 AN: 68840

European-Finnish (FIN) AF: 0.0000257 AC: 1 AN: 38918

Middle Eastern (MID) AF: 0.000351 AC: 1 AN: 2848

European-Non Finnish (NFE) AF: 0.0000599 AC: 40 AN: 667662

Other (OTH) AF: 0.000126 AC: 5 AN: 39694

GnomAD4 genome AF: 0.0000612 AC: 8 AN: 130800 Hom.: 0 Cov.: 24 AF XY: 0.000128 AC XY: 8 AN XY: 62618

African (AFR) AF: 0.000123 AC: 4 AN: 32546

American (AMR) AF: 0.00 AC: 0 AN: 12714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3216

East Asian (EAS) AF: 0.000222 AC: 1 AN: 4506

South Asian (SAS) AF: 0.00 AC: 0 AN: 3994

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8150

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 266

European-Non Finnish (NFE) AF: 0.0000478 AC: 3 AN: 62790

Other (OTH) AF: 0.00 AC: 0 AN: 1790

Alfa AF: 0.00198 Hom.: 1

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Congenital myasthenic syndrome 8 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.32
DANN	Benign	0.64
PhyloP100		-2.6

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000022
dbscSNV1_RF	Benign	0.054
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: rs199977575; hg19: chr1-984445;