chr1-1043540-C-A

Position:

• chr1-1043540-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The ENST00000379370.7(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. 12/21 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. R536C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: AGRN ENST00000379370.7 missense, splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.84

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AGRN	NM_198576.4	c.1606C>A	p.Arg536Ser	missense_variant, splice_region_variant	9/36	ENST00000379370.7	NP_940978.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AGRN	ENST00000379370.7	c.1606C>A	p.Arg536Ser	missense_variant, splice_region_variant	9/36	1	NM_198576.4	ENSP00000368678	P1
AGRN	ENST00000651234.1	c.1291C>A	p.Arg431Ser	missense_variant, splice_region_variant	8/38			ENSP00000499046
AGRN	ENST00000652369.1	c.1291C>A	p.Arg431Ser	missense_variant, splice_region_variant	8/35			ENSP00000498543
AGRN	ENST00000620552.4	c.1192C>A	p.Arg398Ser	missense_variant, splice_region_variant	9/39	5		ENSP00000484607

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
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;T
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.33	T;T
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	0.78	N;.
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.34	N;.
REVEL	Benign	0.21
Sift	Benign	0.75	T;.
Sift4G	Benign	0.62	T;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

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

Publications

LitVar

Other links and lift over

dbSNP: rs745663789; hg19: chr1-978920;