1-1053938-C-T

Variant names:

• chr1-1053938-C-T
• rs771364268
• NM_198576.4:c.5837C>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BP6

The NM_198576.4(AGRN):​c.5837C>T​(p.Pro1946Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000895 in 1,452,104 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P1946P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000090 (0 hom.)
• Consequence: AGRN NM_198576.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.851
• 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.

• BP4: Computational evidence support a benign effect (MetaRNN=0.12114629).
• BP6: Variant 1-1053938-C-T is Benign according to our data. Variant chr1-1053938-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 541146.

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.5837C>T	p.Pro1946Leu	missense	Exon 34 of 36	NP_940978.2
	AGRN	NM_001305275.2		c.5906C>T	p.Pro1969Leu	missense	Exon 37 of 39	NP_001292204.1	O00468-1
	AGRN	NM_001364727.2		c.5534C>T	p.Pro1845Leu	missense	Exon 34 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.5837C>T	p.Pro1946Leu	missense	Exon 34 of 36	ENSP00000368678.2	O00468-6
	AGRN	ENST00000461111.1	TSL:1	n.1953C>T		non_coding_transcript_exon	Exon 1 of 3
	AGRN	ENST00000651234.1		c.5591C>T	p.Pro1864Leu	missense	Exon 36 of 38	ENSP00000499046.1	A0A494C1I6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000429 AC: 1 AN: 233224 AF XY: 0.00000790

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000957

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000895 AC: 13 AN: 1452104 Hom.: 0 Cov.: 35 AF XY: 0.00000693 AC XY: 5 AN XY: 721608

African (AFR) AF: 0.00 AC: 0 AN: 33362

American (AMR) AF: 0.00 AC: 0 AN: 43546

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25950

East Asian (EAS) AF: 0.00 AC: 0 AN: 39328

South Asian (SAS) AF: 0.00 AC: 0 AN: 84714

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51744

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5052

European-Non Finnish (NFE) AF: 0.0000117 AC: 13 AN: 1108408

Other (OTH) AF: 0.00 AC: 0 AN: 60000

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000658 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000826 AC: 1

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	AGRN-related disorder (1)
-	1	-	Congenital myasthenic syndrome 8 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	15
DANN	Uncertain	0.99
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.24	N
LIST_S2	Uncertain	0.87	D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-0.81	T
PhyloP100		0.85
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-3.6	D
REVEL	Benign	0.093
Sift	Benign	0.12	T
Sift4G	Uncertain	0.018	D
Vest4		0.20
MVP		0.39
MPC		0.17
ClinPred		0.11	T
GERP RS		1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.45
Mutation Taster		=90/10	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: rs771364268; hg19: chr1-989318;