rs4275402

Variant names:

• chr1-1054900-C-G
• rs4275402
• NM_198576.4:c.6057C>G

Your query was ambiguous. Multiple possible variants found:

• chr1-1054900-C-G
• chr1-1054900-C-T
• chr1-1054900-C-A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_198576.4(AGRN):​c.6057C>G​(p.Asp2019Glu) variant causes a missense change involving the alteration of a non-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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D2019N) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 34)
• Consequence: AGRN NM_198576.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.712
• Publications: 0 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: DEFINITIVE, STRONG Submitted by: ClinGen, 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

ENSG00000242590 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.767

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGRN	NM_198576.4	MANE Select	c.6057C>G	p.Asp2019Glu	missense	Exon 36 of 36	NP_940978.2
	AGRN	NM_001305275.2		c.6126C>G	p.Asp2042Glu	missense	Exon 39 of 39	NP_001292204.1	O00468-1
	AGRN	NM_001364727.2		c.5754C>G	p.Asp1918Glu	missense	Exon 36 of 36	NP_001351656.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGRN	ENST00000379370.7	TSL:1 MANE Select	c.6057C>G	p.Asp2019Glu	missense	Exon 36 of 36	ENSP00000368678.2	O00468-6
	AGRN	ENST00000461111.1	TSL:1	n.2173C>G		non_coding_transcript_exon	Exon 3 of 3
	AGRN	ENST00000651234.1		c.5811C>G	p.Asp1937Glu	missense	Exon 38 of 38	ENSP00000499046.1	A0A494C1I6

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 88

GnomAD4 genome Cov.: 34

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Congenital myasthenic syndrome 8 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.097	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	3.5
DANN	Uncertain	0.99
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.42	N
LIST_S2	Benign	0.84	T
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.77	D
MetaSVM	Benign	-0.45	T
PhyloP100		-0.71
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-2.5	N
REVEL	Uncertain	0.38
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.0030	D
Vest4		0.44
MVP		0.58
MPC		0.54
ClinPred		0.98	D
GERP RS		-6.2
gMVP		0.61
Mutation Taster		=69/31	polymorphism

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: rs4275402; hg19: chr1-990280;