1-1051336-C-T

Variant names:

• chr1-1051336-C-T
• rs141463750
• NM_198576.4:c.5337C>T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP6_Very_Strong BP7

The NM_198576.4(AGRN):​c.5337C>T​(p.Ala1779Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000778 in 1,555,200 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A1779A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00031 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000053 (0 hom.)
• Consequence: AGRN NM_198576.4 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -4.16
• 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: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.02).
• BP6: Variant 1-1051336-C-T is Benign according to our data. Variant chr1-1051336-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 263196.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.16 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.5337C>T	p.Ala1779Ala	synonymous	Exon 31 of 36	NP_940978.2
	AGRN	NM_001305275.2		c.5349C>T	p.Ala1783Ala	synonymous	Exon 32 of 39	NP_001292204.1	O00468-1
	AGRN	NM_001364727.2		c.5034C>T	p.Ala1678Ala	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.5337C>T	p.Ala1779Ala	synonymous	Exon 31 of 36	ENSP00000368678.2	O00468-6
	AGRN	ENST00000651234.1		c.5034C>T	p.Ala1678Ala	synonymous	Exon 31 of 38	ENSP00000499046.1	A0A494C1I6
	AGRN	ENST00000652369.2		c.5022C>T	p.Ala1674Ala	synonymous	Exon 30 of 35	ENSP00000498543.1	A0A494C0G5

Frequencies

GnomAD3 genomes AF: 0.000314 AC: 47 AN: 149620 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00109

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000149

Gnomad OTH AF: 0.000483

GnomAD2 exomes AF: 0.000153 AC: 27 AN: 176520 AF XY: 0.000116

Gnomad AFR exome AF: 0.00160

Gnomad AMR exome AF: 0.000337

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000526 AC: 74 AN: 1405580 Hom.: 0 Cov.: 37 AF XY: 0.0000504 AC XY: 35 AN XY: 694726

African (AFR) AF: 0.00129 AC: 42 AN: 32560

American (AMR) AF: 0.000240 AC: 9 AN: 37440

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24870

East Asian (EAS) AF: 0.00 AC: 0 AN: 37026

South Asian (SAS) AF: 0.0000248 AC: 2 AN: 80542

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46676

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5440

European-Non Finnish (NFE) AF: 0.0000148 AC: 16 AN: 1082990

Other (OTH) AF: 0.0000862 AC: 5 AN: 58036

GnomAD4 genome AF: 0.000314 AC: 47 AN: 149620 Hom.: 0 Cov.: 33 AF XY: 0.000301 AC XY: 22 AN XY: 73038

African (AFR) AF: 0.00109 AC: 45 AN: 41110

American (AMR) AF: 0.00 AC: 0 AN: 15126

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3436

East Asian (EAS) AF: 0.00 AC: 0 AN: 4926

South Asian (SAS) AF: 0.00 AC: 0 AN: 4616

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9938

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000149 AC: 1 AN: 67202

Other (OTH) AF: 0.000483 AC: 1 AN: 2070

Alfa AF: 0.000264 Hom.: 0

Bravo AF: 0.000431

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.024
DANN	Benign	0.83
PhyloP100		-4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Mutation Taster		=100/0	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: rs141463750; hg19: chr1-986716;