rs4275402

chr1-1054900-C-Achr1-1054900-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.6057C>A(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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. 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: Not reported in ClinVar
• Conservation: PhyloP100: -0.712

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, 0.77

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AGRN	NM_198576.4	c.6057C>A	p.Asp2019Glu	missense_variant	36/36	ENST00000379370.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AGRN	ENST00000379370.7	c.6057C>A	p.Asp2019Glu	missense_variant	36/36	1	NM_198576.4	P1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 88

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.097	T
BayesDel_noAF	Benign	-0.38
Cadd	Benign	3.3
Dann	Uncertain	0.99
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.46	N
LIST_S2	Benign	0.84	T;T
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.77	D;D
MetaSVM	Benign	-0.45	T
MutationTaster	Benign	0.00022	P
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-2.5	N;.
REVEL	Uncertain	0.39
Sift	Uncertain	0.0060	D;.
Sift4G	Uncertain	0.0030	D;D
Vest4		0.44
MVP		0.58
MPC		0.54
ClinPred		0.98	D
GERP RS		-6.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.5
gMVP		0.61

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

LitVar

Other links and lift over

dbSNP: rs4275402; hg19: chr1-990280;