1-1047841-C-G

Position:

• chr1-1047841-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_198576.4(AGRN):​c.3697C>G​(p.Arg1233Gly) 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. 13/19 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. R1233W) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: AGRN NM_198576.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.44

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23023298).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AGRN	NM_198576.4	c.3697C>G	p.Arg1233Gly	missense_variant	22/36	ENST00000379370.7	NP_940978.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AGRN	ENST00000379370.7	c.3697C>G	p.Arg1233Gly	missense_variant	22/36	1	NM_198576.4	ENSP00000368678.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	20
DANN	Uncertain	0.98
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.18	N
LIST_S2	Uncertain	0.87	D;D
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.23	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L;.
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-2.3	N;.
REVEL	Benign	0.055
Sift	Benign	0.097	T;.
Sift4G	Uncertain	0.028	D;D
Vest4		0.40
MutPred		0.57		Loss of stability (P = 0.0375);.;
MVP		0.53
MPC		0.54
ClinPred		0.24	T
GERP RS		0.49
gMVP		0.42

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: rs147673996; hg19: chr1-983221;