1-1051257-C-T

Variant names:

• chr1-1051257-C-T
• rs748126752
• NM_198576.4:c.5258C>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_198576.4(AGRN):​c.5258C>T​(p.Pro1753Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000329 in 1,581,646 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. P1753P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000034 (1 hom.)
• Consequence: AGRN NM_198576.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.69

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.4090562).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGRN	NM_198576.4	c.5258C>T	p.Pro1753Leu	missense_variant	Exon 31 of 36	ENST00000379370.7	NP_940978.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGRN	ENST00000379370.7	c.5258C>T	p.Pro1753Leu	missense_variant	Exon 31 of 36	1	NM_198576.4	ENSP00000368678.2
AGRN	ENST00000651234.1	c.4955C>T	p.Pro1652Leu	missense_variant	Exon 31 of 38			ENSP00000499046.1
AGRN	ENST00000652369.1	c.4943C>T	p.Pro1648Leu	missense_variant	Exon 30 of 35			ENSP00000498543.1
AGRN	ENST00000620552.4	c.4856C>T	p.Pro1619Leu	missense_variant	Exon 32 of 39	5		ENSP00000484607.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152172 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000154 AC: 3 AN: 194292 Hom.: 0 AF XY: 0.00000954 AC XY: 1 AN XY: 104832

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000686

Gnomad SAS exome AF: 0.0000398

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000120

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000343 AC: 49 AN: 1429474 Hom.: 1 Cov.: 36 AF XY: 0.0000282 AC XY: 20 AN XY: 708158

Gnomad4 AFR exome AF: 0.0000304

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000123

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000419

Gnomad4 OTH exome AF: 0.0000169

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152172 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74324

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000661 Hom.: 0

Bravo AF: 0.0000453

ExAC AF: 0.0000168 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Congenital myasthenic syndrome 8 Uncertain:1

Oct 25, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1753 of the AGRN protein (p.Pro1753Leu). 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: 474147). 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: "Benign"; 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	Benign	-0.070	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	22
DANN	Uncertain	1.0
Eigen	Benign	0.17
Eigen_PC	Benign	0.18
FATHMM_MKL	Benign	0.46	N
LIST_S2	Uncertain	0.90	D;T
M_CAP	Pathogenic	0.31	D
MetaRNN	Benign	0.41	T;T
MetaSVM	Benign	-0.46	T
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-5.2	D;.
REVEL	Benign	0.26
Sift	Uncertain	0.012	D;.
Sift4G	Uncertain	0.059	T;T
Vest4		0.39
MVP		0.71
MPC		0.25
ClinPred		0.65	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.43

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

Publications

LitVar

Other links and lift over

dbSNP: rs748126752; hg19: chr1-986637;