rs201346452

Variant names:

• chr1-1049046-C-A
• rs201346452
• NM_198576.4:c.4285C>A

Your query was ambiguous. Multiple possible variants found:

• chr1-1049046-C-A
• chr1-1049046-C-G
• chr1-1049046-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_198576.4(AGRN):​c.4285C>A​(p.Arg1429Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000213 in 1,408,418 control chromosomes in the GnomAD database, with no homozygous occurrence. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1429H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 25)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: AGRN NM_198576.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.72
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGRN	NM_198576.4	c.4285C>A	p.Arg1429Ser	missense_variant	Exon 24 of 36	ENST00000379370.7	NP_940978.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGRN	ENST00000379370.7	c.4285C>A	p.Arg1429Ser	missense_variant	Exon 24 of 36	1	NM_198576.4	ENSP00000368678.2

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD2 exomes AF: 0.00000627 AC: 1 AN: 159610 AF XY: 0.0000115

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: 0.00

Gnomad OTH exome AF: 0.000224

GnomAD4 exome AF: 0.00000213 AC: 3 AN: 1408418 Hom.: 0 Cov.: 51 AF XY: 0.00000144 AC XY: 1 AN XY: 696262

African (AFR) AF: 0.00 AC: 0 AN: 31848

American (AMR) AF: 0.00 AC: 0 AN: 37960

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25200

East Asian (EAS) AF: 0.00 AC: 0 AN: 36932

South Asian (SAS) AF: 0.00 AC: 0 AN: 80092

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47878

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4068

European-Non Finnish (NFE) AF: 0.00000276 AC: 3 AN: 1086250

Other (OTH) AF: 0.00 AC: 0 AN: 58190

GnomAD4 genome Cov.: 25

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Congenital myasthenic syndrome 8 Uncertain:1

Aug 03, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with AGRN-related disease. While this variant is not present in population databases, the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This sequence change replaces arginine with serine at codon 1429 of the AGRN protein (p.Arg1429Ser). The arginine residue is weakly conserved and there is a moderate physicochemical difference between arginine and serine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.019	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	19
DANN	Benign	0.97
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.23	N
LIST_S2	Uncertain	0.94	D;D
M_CAP	Pathogenic	0.54	D
MetaRNN	Uncertain	0.62	D;D
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	1.9	L;.
PhyloP100		1.7
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.96	N;.
REVEL	Benign	0.26
Sift	Benign	0.32	T;.
Sift4G	Benign	0.43	T;T
Vest4		0.49
MutPred		0.70		Gain of loop (P = 0.1069);.;
MVP		0.80
MPC		0.24
ClinPred		0.13	T
GERP RS		2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.68
Mutation Taster		=93/7	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: rs201346452; hg19: chr1-984426;