chr1-1050277-G-A

Position:

• chr1-1050277-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000379370.7(AGRN):​c.4924G>A​(p.Gly1642Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00021 in 1,613,064 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. G1642G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00022 (0 hom.)
• Consequence: AGRN ENST00000379370.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.20

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24131757).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AGRN	NM_198576.4	c.4924G>A	p.Gly1642Ser	missense_variant	28/36	ENST00000379370.7	NP_940978.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AGRN	ENST00000379370.7	c.4924G>A	p.Gly1642Ser	missense_variant	28/36	1	NM_198576.4	ENSP00000368678	P1
AGRN	ENST00000651234.1	c.4609G>A	p.Gly1537Ser	missense_variant	27/38			ENSP00000499046
AGRN	ENST00000652369.1	c.4609G>A	p.Gly1537Ser	missense_variant	27/35			ENSP00000498543
AGRN	ENST00000620552.4	c.4510G>A	p.Gly1504Ser	missense_variant	28/39	5		ENSP00000484607

Frequencies

GnomAD3 genomes AF: 0.0000790 AC: 12 AN: 151982 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000967

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000118

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000108 AC: 27 AN: 249770 Hom.: 0 AF XY: 0.000133 AC XY: 18 AN XY: 135478

Gnomad AFR exome AF: 0.000125

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000550

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.000195

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000224 AC: 327 AN: 1460964 Hom.: 0 Cov.: 34 AF XY: 0.000228 AC XY: 166 AN XY: 726782

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.0000761

Gnomad4 NFE exome AF: 0.000276

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.0000789 AC: 12 AN: 152100 Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6 AN XY: 74370

Gnomad4 AFR AF: 0.0000964

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000180 Hom.: 0

Bravo AF: 0.0000529

ExAC AF: 0.0000824 AC: 10

EpiCase AF: 0.000327

EpiControl AF: 0.000237

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

Labcorp Genetics (formerly Invitae), Labcorp

Jul 19, 2022

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1642 of the AGRN protein (p.Gly1642Ser). This variant is present in population databases (rs200051701, gnomAD 0.02%). 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: 572154). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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	-0.15	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	23
DANN	Benign	0.89
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.84	T;T
M_CAP	Pathogenic	0.49	D
MetaRNN	Benign	0.24	T;T
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Uncertain	2.3	M;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.52	T
PROVEAN	Pathogenic	-4.6	D;.
REVEL	Uncertain	0.42
Sift	Uncertain	0.025	D;.
Sift4G	Benign	0.094	T;T
Vest4		0.26
MVP		0.81
MPC		0.54
ClinPred		0.22	T
GERP RS		3.1
gMVP		0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs200051701; hg19: chr1-985657;