Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_198576.4(AGRN):c.1123G>A(p.Ala375Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 13/21 in silico tools predict a benign 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. A375S) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 31)

Consequence

AGRN
NM_198576.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.49

Publications

13 publications found

Variant links:

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]

AGRN Gene-Disease associations (from GenCC):

congenital myasthenic syndrome 8
Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
presynaptic congenital myasthenic syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
postsynaptic congenital myasthenic syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

AGRN links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198576.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
AGRN	NM_198576.4	MANE Select	c.1123G>A	p.Ala375Thr	missense	Exon 6 of 36	NP_940978.2
AGRN	NM_001305275.2		c.1123G>A	p.Ala375Thr	missense	Exon 6 of 39	NP_001292204.1
AGRN	NM_001364727.2		c.808G>A	p.Ala270Thr	missense	Exon 5 of 36	NP_001351656.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
AGRN	ENST00000379370.7	TSL:1 MANE Select	c.1123G>A	p.Ala375Thr	missense	Exon 6 of 36	ENSP00000368678.2
AGRN	ENST00000651234.1		c.808G>A	p.Ala270Thr	missense	Exon 5 of 38	ENSP00000499046.1
AGRN	ENST00000652369.2		c.808G>A	p.Ala270Thr	missense	Exon 5 of 35	ENSP00000498543.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Congenital myasthenic syndrome 8 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.082

BayesDel_noAF

Benign

-0.36

CADD

Benign

(source)

DANN

Uncertain

1.0

Eigen

Benign

-0.042

Eigen_PC

Benign

-0.19

FATHMM_MKL

Benign

0.13

LIST_S2

Uncertain

0.91

M_CAP

Uncertain

0.18

MetaRNN

Uncertain

0.58

MetaSVM

Benign

-0.53

MutationAssessor

Benign

1.3

PhyloP100

1.5

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-1.2

REVEL

Benign

0.28

Sift

Uncertain

0.020

Sift4G

Benign

0.40

Vest4

0.47

MutPred

0.60

Gain of phosphorylation at A375 (P = 0.0814)

MVP

0.78

MPC

1.1

ClinPred

0.65

GERP RS

4.7

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.7

gMVP

0.23

Mutation Taster

=89/11

polymorphism

(source)

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

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1-1041648-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over