NM_198576.4:c.1130G>C

Variant names:

• chr1-1041655-G-C
• NM_198576.4:c.1130G>C

Variant summary

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

The NM_198576.4(AGRN):​c.1130G>C​(p.Arg377Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,458,934 control chromosomes in the GnomAD database, with no homozygous occurrence. 11/19 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. R377Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: AGRN NM_198576.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.733

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGRN	NM_198576.4	c.1130G>C	p.Arg377Pro	missense_variant	Exon 6 of 36	ENST00000379370.7	NP_940978.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGRN	ENST00000379370.7	c.1130G>C	p.Arg377Pro	missense_variant	Exon 6 of 36	1	NM_198576.4	ENSP00000368678.2
AGRN	ENST00000651234.1	c.815G>C	p.Arg272Pro	missense_variant	Exon 5 of 38			ENSP00000499046.1
AGRN	ENST00000652369.1	c.815G>C	p.Arg272Pro	missense_variant	Exon 5 of 35			ENSP00000498543.1
AGRN	ENST00000620552.4	c.716G>C	p.Arg239Pro	missense_variant	Exon 6 of 39	5		ENSP00000484607.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1458934 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 725696

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	0.010	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	18
DANN	Benign	0.96
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.16	N
LIST_S2	Uncertain	0.89	D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Uncertain	0.66	D;D
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	1.8	L;.
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-2.2	N;.
REVEL	Uncertain	0.36
Sift	Benign	0.12	T;.
Sift4G	Benign	0.19	T;T
Vest4		0.66
MutPred		0.57		Loss of MoRF binding (P = 0.0059);.;
MVP		0.79
MPC		1.3
ClinPred		0.39	T
GERP RS		-0.76
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.1
gMVP		0.68

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-977035;