rs2275812

Variant names:

• chr1-1050066-G-A
• rs2275812
• NM_198576.4:c.4879+29G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-1050066-G-A
• chr1-1050066-G-C
• chr1-1050066-G-T

Variant summary

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

The NM_198576.4(AGRN):​c.4879+29G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000821 in 1,217,332 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 28)
  • Exomes 𝑓: 8.2e-7 (0 hom.)
• Consequence: AGRN NM_198576.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.24
• 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=-0.88).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGRN	NM_198576.4	c.4879+29G>A		intron_variant	Intron 27 of 35	ENST00000379370.7	NP_940978.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGRN	ENST00000379370.7	c.4879+29G>A		intron_variant	Intron 27 of 35	1	NM_198576.4	ENSP00000368678.2
AGRN	ENST00000651234.1	c.4564+29G>A		intron_variant	Intron 26 of 37			ENSP00000499046.1
AGRN	ENST00000652369.2	c.4564+29G>A		intron_variant	Intron 26 of 34			ENSP00000498543.1
AGRN	ENST00000620552.4	c.4465+29G>A		intron_variant	Intron 27 of 38	5		ENSP00000484607.1

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome AF: 8.21e-7 AC: 1 AN: 1217332 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 603846

⚠️ 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: 25214

American (AMR) AF: 0.00 AC: 0 AN: 33352

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22922

East Asian (EAS) AF: 0.00 AC: 0 AN: 33286

South Asian (SAS) AF: 0.00 AC: 0 AN: 73160

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43838

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3660

European-Non Finnish (NFE) AF: 0.00000107 AC: 1 AN: 930822

Other (OTH) AF: 0.00 AC: 0 AN: 51078

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 28

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.19
DANN	Benign	0.75
PhyloP100		-1.2

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2275812; hg19: chr1-985446;