rs199977575

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr1-1049065-C-G
• chr1-1049065-C-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000379370.7(AGRN):​c.4298+6C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000109 in 918,890 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0000011 (0 hom.)
• Consequence: AGRN ENST00000379370.7 splice_region, intron
• Scores: Splicing: ADA: 0.00004617
• Clinical Significance: Not reported in ClinVar
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000379370.7. 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>G		splice_region intron	N/A	NP_940978.2
	AGRN	NM_001305275.2		c.4298+6C>G		splice_region intron	N/A	NP_001292204.1
	AGRN	NM_001364727.2		c.3983+6C>G		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>G		splice_region intron	N/A	ENSP00000368678.2
	AGRN	ENST00000651234.1		c.3983+6C>G		splice_region intron	N/A	ENSP00000499046.1
	AGRN	ENST00000652369.2		c.3983+6C>G		splice_region intron	N/A	ENSP00000498543.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 0.00000109 AC: 1 AN: 918890 Hom.: 0 Cov.: 39 AF XY: 0.00000215 AC XY: 1 AN XY: 465570

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

African (AFR) AF: 0.00 AC: 0 AN: 18240

American (AMR) AF: 0.00 AC: 0 AN: 33042

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19670

East Asian (EAS) AF: 0.00 AC: 0 AN: 29964

South Asian (SAS) AF: 0.00 AC: 0 AN: 68842

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38918

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2848

European-Non Finnish (NFE) AF: 0.00000150 AC: 1 AN: 667672

Other (OTH) AF: 0.00 AC: 0 AN: 39694

⚠️ 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.: 24

Alfa AF: 0.00 Hom.: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.15
DANN	Benign	0.38
PhyloP100		-2.6

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000046
dbscSNV1_RF	Benign	0.014
SpliceAI score (max)		0.030		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;