rs587777298

Variant names:

• chr1-1050763-G-C
• NM_198576.4:c.5179G>C

Your query was ambiguous. Multiple possible variants found:

• chr1-1050763-G-C
• chr1-1050763-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PM5 PP3_Moderate

The NM_198576.4(AGRN):​c.5179G>C​(p.Val1727Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000689 in 1,451,708 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. V1727F) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: AGRN NM_198576.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.93

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-1050763-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 126555.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.843

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGRN	NM_198576.4	c.5179G>C	p.Val1727Leu	missense_variant	Exon 30 of 36	ENST00000379370.7	NP_940978.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGRN	ENST00000379370.7	c.5179G>C	p.Val1727Leu	missense_variant	Exon 30 of 36	1	NM_198576.4	ENSP00000368678.2
AGRN	ENST00000651234.1	c.4864G>C	p.Val1622Leu	missense_variant	Exon 29 of 38			ENSP00000499046.1
AGRN	ENST00000652369.1	c.4864G>C	p.Val1622Leu	missense_variant	Exon 29 of 35			ENSP00000498543.1
AGRN	ENST00000620552.4	c.4765G>C	p.Val1589Leu	missense_variant	Exon 30 of 39	5		ENSP00000484607.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1451708 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 721960

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: 9.01e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.089	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	23
DANN	Uncertain	0.97
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.84	D;D
MetaSVM	Uncertain	0.28	D
MutationAssessor	Uncertain	2.0	M;.
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-2.1	N;.
REVEL	Pathogenic	0.68
Sift	Benign	0.12	T;.
Sift4G	Uncertain	0.0070	D;D
Vest4		0.66
MutPred		0.63		Loss of catalytic residue at V1727 (P = 0.1319);.;
MVP		0.81
MPC		0.46
ClinPred		0.79	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: chr1-986143;