1-1051307-G-A

Variant names:

• chr1-1051307-G-A
• rs141464249
• NM_198576.4:c.5308G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_198576.4(AGRN):​c.5308G>A​(p.Asp1770Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000102 in 1,572,062 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00010 (0 hom.)
• Consequence: AGRN NM_198576.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.42
• 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: Uncertain_significance. The variant received 0 ACMG points.

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.5308G>A	p.Asp1770Asn	missense	Exon 31 of 36	NP_940978.2
	AGRN	NM_001305275.2		c.5320G>A	p.Asp1774Asn	missense	Exon 32 of 39	NP_001292204.1	O00468-1
	AGRN	NM_001364727.2		c.5005G>A	p.Asp1669Asn	missense	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.5308G>A	p.Asp1770Asn	missense	Exon 31 of 36	ENSP00000368678.2	O00468-6
	AGRN	ENST00000651234.1		c.5005G>A	p.Asp1669Asn	missense	Exon 31 of 38	ENSP00000499046.1	A0A494C1I6
	AGRN	ENST00000652369.2		c.4993G>A	p.Asp1665Asn	missense	Exon 30 of 35	ENSP00000498543.1	A0A494C0G5

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152138 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000668 AC: 12 AN: 179742 AF XY: 0.0000725

Gnomad AFR exome AF: 0.000186

Gnomad AMR exome AF: 0.0000366

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000124

Gnomad NFE exome AF: 0.0000944

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000100 AC: 142 AN: 1419924 Hom.: 0 Cov.: 36 AF XY: 0.0000968 AC XY: 68 AN XY: 702398

African (AFR) AF: 0.000122 AC: 4 AN: 32770

American (AMR) AF: 0.0000259 AC: 1 AN: 38570

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25364

East Asian (EAS) AF: 0.0000265 AC: 1 AN: 37792

South Asian (SAS) AF: 0.00 AC: 0 AN: 80776

European-Finnish (FIN) AF: 0.0000616 AC: 3 AN: 48682

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5574

European-Non Finnish (NFE) AF: 0.000115 AC: 126 AN: 1091556

Other (OTH) AF: 0.000119 AC: 7 AN: 58840

GnomAD4 genome AF: 0.000125 AC: 19 AN: 152138 Hom.: 0 Cov.: 33 AF XY: 0.000108 AC XY: 8 AN XY: 74306

African (AFR) AF: 0.000241 AC: 10 AN: 41422

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000494 Hom.: 0

Bravo AF: 0.0000982

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Congenital myasthenic syndrome 8 (1)
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
PhyloP100		4.4
gMVP		0.66
Mutation Taster		=46/54	disease causing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs141464249; hg19: chr1-986687; COSMIC: COSV99062190; COSMIC: COSV99062190;