1-1051333-T-G

Variant names:

• chr1-1051333-T-G
• rs1553178299
• NM_198576.4:c.5334T>G

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_198576.4(AGRN):​c.5334T>G​(p.Ala1778Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000707 in 1,414,004 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. Synonymous variant affecting the same amino acid position (i.e. A1778A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: AGRN NM_198576.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -5.86
• 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: 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 -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (REVEL=0.011).
• BP7: Synonymous conserved (PhyloP=-5.86 with no splicing effect.

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.5334T>G	p.Ala1778Ala	synonymous	Exon 31 of 36	NP_940978.2
	AGRN	NM_001305275.2		c.5346T>G	p.Ala1782Ala	synonymous	Exon 32 of 39	NP_001292204.1	O00468-1
	AGRN	NM_001364727.2		c.5031T>G	p.Ala1677Ala	synonymous	Exon 31 of 36	NP_001351656.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGRN	ENST00000379370.7	TSL:1 MANE Select	c.5334T>G	p.Ala1778Ala	synonymous	Exon 31 of 36	ENSP00000368678.2	O00468-6
	AGRN	ENST00000651234.1		c.5031T>G	p.Ala1677Ala	synonymous	Exon 31 of 38	ENSP00000499046.1	A0A494C1I6
	AGRN	ENST00000652369.2		c.5019T>G	p.Ala1673Ala	synonymous	Exon 30 of 35	ENSP00000498543.1	A0A494C0G5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.07e-7 AC: 1 AN: 1414004 Hom.: 0 Cov.: 36 AF XY: 0.00000143 AC XY: 1 AN XY: 699084

African (AFR) AF: 0.0000305 AC: 1 AN: 32770

American (AMR) AF: 0.00 AC: 0 AN: 37666

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25238

East Asian (EAS) AF: 0.00 AC: 0 AN: 37606

South Asian (SAS) AF: 0.00 AC: 0 AN: 80620

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47824

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5512

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1088226

Other (OTH) AF: 0.00 AC: 0 AN: 58542

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.13
DANN	Benign	0.53
PhyloP100		-5.9
Mutation Taster		=87/13	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: rs1553178299; hg19: chr1-986713;