1-1049791-C-T

Variant names:

• chr1-1049791-C-T
• rs115019873
• NM_198576.4:c.4740C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The ENST00000379370.7(AGRN):​c.4740C>T​(p.Arg1580Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00312 in 1,595,942 control chromosomes in the GnomAD database, including 130 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (63 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (67 hom.)
• Consequence: AGRN ENST00000379370.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.224
• Publications: 1 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 1-1049791-C-T is Benign according to our data. Variant chr1-1049791-C-T is described in ClinVar as Benign. ClinVar VariationId is 128311.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.224 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0545 is higher than 0.05.

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.4740C>T	p.Arg1580Arg	synonymous	Exon 26 of 36	NP_940978.2
	AGRN	NM_001305275.2		c.4740C>T	p.Arg1580Arg	synonymous	Exon 26 of 39	NP_001292204.1
	AGRN	NM_001364727.2		c.4425C>T	p.Arg1475Arg	synonymous	Exon 25 of 36	NP_001351656.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGRN	ENST00000379370.7	TSL:1 MANE Select	c.4740C>T	p.Arg1580Arg	synonymous	Exon 26 of 36	ENSP00000368678.2
	AGRN	ENST00000651234.1		c.4425C>T	p.Arg1475Arg	synonymous	Exon 25 of 38	ENSP00000499046.1
	AGRN	ENST00000652369.2		c.4425C>T	p.Arg1475Arg	synonymous	Exon 25 of 35	ENSP00000498543.1

Frequencies

GnomAD3 genomes AF: 0.0162 AC: 2463 AN: 151724 Hom.: 63 Cov.: 32

Gnomad AFR AF: 0.0566

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00564

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000221

Gnomad OTH AF: 0.0105

GnomAD2 exomes AF: 0.00392 AC: 835 AN: 212948 AF XY: 0.00311

Gnomad AFR exome AF: 0.0595

Gnomad AMR exome AF: 0.00248

Gnomad ASJ exome AF: 0.000224

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000154

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00174 AC: 2510 AN: 1444100 Hom.: 67 Cov.: 44 AF XY: 0.00150 AC XY: 1073 AN XY: 716942

African (AFR) AF: 0.0617 AC: 2044 AN: 33148

American (AMR) AF: 0.00264 AC: 111 AN: 42086

Ashkenazi Jewish (ASJ) AF: 0.000195 AC: 5 AN: 25630

East Asian (EAS) AF: 0.0000769 AC: 3 AN: 39034

South Asian (SAS) AF: 0.000130 AC: 11 AN: 84806

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50266

Middle Eastern (MID) AF: 0.00316 AC: 18 AN: 5700

European-Non Finnish (NFE) AF: 0.0000897 AC: 99 AN: 1103850

Other (OTH) AF: 0.00368 AC: 219 AN: 59580

GnomAD4 genome AF: 0.0162 AC: 2462 AN: 151842 Hom.: 63 Cov.: 32 AF XY: 0.0161 AC XY: 1193 AN XY: 74260

African (AFR) AF: 0.0564 AC: 2335 AN: 41402

American (AMR) AF: 0.00563 AC: 86 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.000289 AC: 1 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5138

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10590

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000221 AC: 15 AN: 67838

Other (OTH) AF: 0.0104 AC: 22 AN: 2110

Alfa AF: 0.000679 Hom.: 2

Bravo AF: 0.0185

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	1	Congenital myasthenic syndrome 8 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	6.7
DANN	Benign	0.44
PhyloP100		-0.22
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs115019873; hg19: chr1-985171;