rs6657048

Positions:

• chr1-1022260-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_198576.4(AGRN):​c.261C>T​(p.Asp87=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0162 in 1,613,184 control chromosomes in the GnomAD database, including 425 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.029 (123 hom., cov: 34)
  • Exomes 𝑓: 0.015 (302 hom.)
• Consequence: AGRN NM_198576.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -2.21

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 1-1022260-C-T is Benign according to our data. Variant chr1-1022260-C-T is described in ClinVar as [Benign]. Clinvar id is 128296.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.21 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0665 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AGRN	NM_198576.4	c.261C>T	p.Asp87=	synonymous_variant	2/36	ENST00000379370.7	NP_940978.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AGRN	ENST00000379370.7	c.261C>T	p.Asp87=	synonymous_variant	2/36	1	NM_198576.4	ENSP00000368678	P1
AGRN	ENST00000620552.4	c.-154C>T		5_prime_UTR_variant	2/39	5		ENSP00000484607

Frequencies

GnomAD3 genomes AF: 0.0288 AC: 4384 AN: 152188 Hom.: 123 Cov.: 34

Gnomad AFR AF: 0.0687

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.0108

Gnomad ASJ AF: 0.0187

Gnomad EAS AF: 0.00538

Gnomad SAS AF: 0.0356

Gnomad FIN AF: 0.00443

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0146

Gnomad OTH AF: 0.0287

GnomAD3 exomes AF: 0.0181 AC: 4549 AN: 250898 Hom.: 102 AF XY: 0.0187 AC XY: 2539 AN XY: 135772

Gnomad AFR exome AF: 0.0726

Gnomad AMR exome AF: 0.00633

Gnomad ASJ exome AF: 0.0168

Gnomad EAS exome AF: 0.00413

Gnomad SAS exome AF: 0.0357

Gnomad FIN exome AF: 0.00508

Gnomad NFE exome AF: 0.0143

Gnomad OTH exome AF: 0.0135

GnomAD4 exome AF: 0.0148 AC: 21676 AN: 1460878 Hom.: 302 Cov.: 33 AF XY: 0.0155 AC XY: 11265 AN XY: 726746

Gnomad4 AFR exome AF: 0.0725

Gnomad4 AMR exome AF: 0.00729

Gnomad4 ASJ exome AF: 0.0187

Gnomad4 EAS exome AF: 0.00189

Gnomad4 SAS exome AF: 0.0363

Gnomad4 FIN exome AF: 0.00644

Gnomad4 NFE exome AF: 0.0124

Gnomad4 OTH exome AF: 0.0167

GnomAD4 genome AF: 0.0288 AC: 4387 AN: 152306 Hom.: 123 Cov.: 34 AF XY: 0.0281 AC XY: 2092 AN XY: 74470

Gnomad4 AFR AF: 0.0686

Gnomad4 AMR AF: 0.0108

Gnomad4 ASJ AF: 0.0187

Gnomad4 EAS AF: 0.00520

Gnomad4 SAS AF: 0.0358

Gnomad4 FIN AF: 0.00443

Gnomad4 NFE AF: 0.0146

Gnomad4 OTH AF: 0.0279

Alfa AF: 0.0186 Hom.: 59

Bravo AF: 0.0307

Asia WGS AF: 0.0190 AC: 67 AN: 3478

EpiCase AF: 0.0172

EpiControl AF: 0.0154

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 03, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 21, 2020	- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Congenital myasthenic syndrome 8 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	0.59
DANN	Benign	0.87
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8

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: rs6657048; hg19: chr1-957640; COSMIC: COSV65070021;