rs745663789

Variant names:

• chr1-1043540-C-A
• rs745663789
• NM_198576.4:c.1606C>A

Your query was ambiguous. Multiple possible variants found:

• chr1-1043540-C-A
• chr1-1043540-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_198576.4(AGRN):​c.1606C>A​(p.Arg536Ser) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000689 in 1,451,560 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R536H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: AGRN NM_198576.4 missense, splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.84
• 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: 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGRN	NM_198576.4	MANE Select	c.1606C>A	p.Arg536Ser	missense splice_region	Exon 9 of 36	NP_940978.2
	AGRN	NM_001305275.2		c.1606C>A	p.Arg536Ser	missense splice_region	Exon 9 of 39	NP_001292204.1
	AGRN	NM_001364727.2		c.1291C>A	p.Arg431Ser	missense splice_region	Exon 8 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.1606C>A	p.Arg536Ser	missense splice_region	Exon 9 of 36	ENSP00000368678.2
	AGRN	ENST00000651234.1		c.1291C>A	p.Arg431Ser	missense splice_region	Exon 8 of 38	ENSP00000499046.1
	AGRN	ENST00000652369.2		c.1291C>A	p.Arg431Ser	missense splice_region	Exon 8 of 35	ENSP00000498543.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1451560 Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1 AN XY: 722576

African (AFR) AF: 0.00 AC: 0 AN: 33468

American (AMR) AF: 0.00 AC: 0 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26112

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43462

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111790

Other (OTH) AF: 0.0000166 AC: 1 AN: 60316

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.0090	T
BayesDel_noAF	Benign	-0.25
CADD	Pathogenic	33
DANN	Benign	0.65
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.16
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.33	T
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	0.78	N
PhyloP100		3.8
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.34	N
REVEL	Benign	0.21
Sift	Benign	0.75	T
Sift4G	Benign	0.62	T
Vest4		0.42
MutPred		0.36		Gain of ubiquitination at K531 (P = 0.041)
MVP		0.85
MPC		0.27
ClinPred		0.37	T
GERP RS		4.2
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.1
gMVP		0.32
Mutation Taster		=69/31	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.91		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.91		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs745663789; hg19: chr1-978920;