rs1256837701

Variant names:

• chr1-1041274-C-A
• NM_198576.4:c.829C>A

Your query was ambiguous. Multiple possible variants found:

• chr1-1041274-C-A
• chr1-1041274-C-G
• chr1-1041274-C-T

Variant summary

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

The NM_198576.4(AGRN):​c.829C>A​(p.Arg277Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000737 in 1,356,818 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 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. R277G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.4e-7 (0 hom.)
• Consequence: AGRN NM_198576.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.751

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.829C>A	p.Arg277Ser	missense_variant	Exon 5 of 36	ENST00000379370.7	NP_940978.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGRN	ENST00000379370.7	c.829C>A	p.Arg277Ser	missense_variant	Exon 5 of 36	1	NM_198576.4	ENSP00000368678.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.37e-7 AC: 1 AN: 1356818 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 669546

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: 9.38e-7

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	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	19
DANN	Benign	0.64
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.50	T;T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.056	T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	-2.4	N;.
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.040	N;.
REVEL	Benign	0.077
Sift	Benign	0.83	T;.
Sift4G	Benign	0.77	T;T
Vest4		0.096
MutPred		0.38		Gain of glycosylation at R277 (P = 0.0064);.;
MVP		0.64
MPC		1.1
ClinPred		0.11	T
GERP RS		1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
gMVP		0.22

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.32		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.32		Position offset: 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: chr1-976654;