rs540580770

Positions:

• chr1-1051809-C-G
• chr1-1051809-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_198576.4(AGRN):​c.5645C>G​(p.Thr1882Ser) 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 benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1882I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: AGRN NM_198576.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.56

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.38808885).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AGRN	NM_198576.4	c.5645C>G	p.Thr1882Ser	missense_variant	33/36	ENST00000379370.7	NP_940978.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AGRN	ENST00000379370.7	c.5645C>G	p.Thr1882Ser	missense_variant	33/36	1	NM_198576.4	ENSP00000368678.2
AGRN	ENST00000651234.1	c.5342C>G	p.Thr1781Ser	missense_variant	33/38			ENSP00000499046.1
AGRN	ENST00000652369.1	c.5330C>G	p.Thr1777Ser	missense_variant	32/35			ENSP00000498543.1
AGRN	ENST00000620552.4	c.5243C>G	p.Thr1748Ser	missense_variant	34/39	5		ENSP00000484607.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 85

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	16
DANN	Benign	0.94
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.46
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.86	D;T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.39	T;T
MetaSVM	Benign	-0.81	T
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.6	N;.
REVEL	Benign	0.21
Sift	Benign	0.38	T;.
Sift4G	Uncertain	0.021	D;D
Vest4		0.36
MVP		0.76
MPC		0.12
ClinPred		0.22	T
GERP RS		3.0
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.1
gMVP		0.37

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-987189;