1-1050575-G-C

Variant names:

• chr1-1050575-G-C
• rs199476396
• NM_198576.4:c.5125G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_198576.4(AGRN):​c.5125G>C​(p.Gly1709Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: AGRN NM_198576.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 9.28
• Publications: 17 publications found

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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.974
• PP5: Variant 1-1050575-G-C is Pathogenic according to our data. Variant chr1-1050575-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 18241.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGRN	NM_198576.4	c.5125G>C	p.Gly1709Arg	missense_variant	Exon 29 of 36	ENST00000379370.7	NP_940978.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGRN	ENST00000379370.7	c.5125G>C	p.Gly1709Arg	missense_variant	Exon 29 of 36	1	NM_198576.4	ENSP00000368678.2
AGRN	ENST00000651234.1	c.4810G>C	p.Gly1604Arg	missense_variant	Exon 28 of 38			ENSP00000499046.1
AGRN	ENST00000652369.2	c.4810G>C	p.Gly1604Arg	missense_variant	Exon 28 of 35			ENSP00000498543.1
AGRN	ENST00000620552.4	c.4711G>C	p.Gly1571Arg	missense_variant	Exon 29 of 39	5		ENSP00000484607.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Congenital myasthenic syndrome 8 Pathogenic:1

Aug 01, 2009

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Congenital myasthenic syndrome Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Uncertain	25
DANN	Uncertain	1.0
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.71	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Uncertain	0.61	D
MutationAssessor	Pathogenic	3.0	M;.
PhyloP100		9.3
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-5.7	D;.
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D;.
Sift4G	Uncertain	0.0020	D;D
Vest4		0.83
MutPred		0.81		Gain of MoRF binding (P = 0.0205);.;
MVP		0.89
MPC		0.63
ClinPred		1.0	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.92
Mutation Taster		=21/79	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs199476396; hg19: chr1-985955;