rs754169694

chr1-1043630-G-Achr1-1043630-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_198576.4(AGRN):c.1696G>A(p.Val566Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000248 in 1,451,200 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: AGRN NM_198576.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.26

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.87

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AGRN	NM_198576.4	c.1696G>A	p.Val566Met	missense_variant	9/36	ENST00000379370.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AGRN	ENST00000379370.7	c.1696G>A	p.Val566Met	missense_variant	9/36	1	NM_198576.4	P1
AGRN	ENST00000651234.1	c.1381G>A	p.Val461Met	missense_variant	8/38
AGRN	ENST00000652369.1	c.1381G>A	p.Val461Met	missense_variant	8/35
AGRN	ENST00000620552.4	c.1282G>A	p.Val428Met	missense_variant	9/39	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000211 AC: 5 AN: 237352 Hom.: 0 AF XY: 0.0000231 AC XY: 3 AN XY: 129866

Gnomad AFR exome AF: 0.0000636

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000110

Gnomad SAS exome AF: 0.0000656

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000248 AC: 36 AN: 1451200 Hom.: 0 Cov.: 35 AF XY: 0.0000221 AC XY: 16 AN XY: 722368

Gnomad4 AFR exome AF: 0.0000897

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000171

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000113

ExAC AF: 0.0000165 AC: 2

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Congenital myasthenic syndrome 8 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 10, 2022

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 566 of the AGRN protein (p.Val566Met). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with AGRN-related conditions. ClinVar contains an entry for this variant (Variation ID: 581790). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
Cadd	Uncertain	25
Dann	Uncertain	1.0
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.87	D;D
MetaSVM	Pathogenic	0.87	D
MutationAssessor	Pathogenic	4.1	H;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-2.4	N;.
REVEL	Pathogenic	0.73
Sift	Uncertain	0.0020	D;.
Sift4G	Uncertain	0.0020	D;D
Vest4		0.54
MutPred		0.80		Gain of disorder (P = 0.0678);.;
MVP		0.86
MPC		0.50
ClinPred		0.59	D
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
gMVP		0.72

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs754169694; hg19: chr1-979010; COSMIC: COSV65067703; COSMIC: COSV65067703;