chr1-1046220-C-T

Position:

• chr1-1046220-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_198576.4(AGRN):​c.2866C>T​(p.Arg956Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000144 in 1,461,376 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R956H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: AGRN NM_198576.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.94

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.839

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AGRN	NM_198576.4	c.2866C>T	p.Arg956Cys	missense_variant	17/36	ENST00000379370.7	NP_940978.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AGRN	ENST00000379370.7	c.2866C>T	p.Arg956Cys	missense_variant	17/36	1	NM_198576.4	ENSP00000368678.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000319 AC: 8 AN: 251064 Hom.: 0 AF XY: 0.0000442 AC XY: 6 AN XY: 135838

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000265

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000144 AC: 21 AN: 1461376 Hom.: 0 Cov.: 39 AF XY: 0.0000151 AC XY: 11 AN XY: 726962

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000153

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000113

ExAC AF: 0.0000330 AC: 4

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 24, 2024

The c.2866C>T (p.R956C) alteration is located in exon 17 (coding exon 17) of the AGRN gene. This alteration results from a C to T substitution at nucleotide position 2866, causing the arginine (R) at amino acid position 956 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Congenital myasthenic syndrome 8 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 04, 2022

This variant is present in population databases (rs751407693, gnomAD 0.006%). 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 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"). ClinVar contains an entry for this variant (Variation ID: 567364). This variant has not been reported in the literature in individuals affected with AGRN-related conditions. This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 956 of the AGRN protein (p.Arg956Cys). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.082	T
BayesDel_noAF	Benign	-0.17
CADD	Pathogenic	28
DANN	Pathogenic	1.0
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Uncertain	0.095	D
MetaRNN	Pathogenic	0.84	D;D
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.8	M;.
PrimateAI	Uncertain	0.52	T
PROVEAN	Pathogenic	-6.9	D;.
REVEL	Benign	0.28
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;D
Vest4		0.74
MutPred		0.60		Gain of ubiquitination at K951 (P = 0.0638);.;
MVP		0.69
MPC		0.61
ClinPred		0.95	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.83

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs751407693; hg19: chr1-981600;