rs17778478

Positions:

• chr1-1051762-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_198576.4(AGRN):​c.5598C>T​(p.Thr1866Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00593 in 1,613,892 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0069 (5 hom., cov: 34)
  • Exomes 𝑓: 0.0058 (28 hom.)
• Consequence: AGRN NM_198576.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.57

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=-0.82).
• BP6: Variant 1-1051762-C-T is Benign according to our data. Variant chr1-1051762-C-T is described in ClinVar as [Benign]. Clinvar id is 128316.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.57 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00685 (1044/152350) while in subpopulation AFR AF= 0.011 (457/41586). AF 95% confidence interval is 0.0102. There are 5 homozygotes in gnomad4. There are 489 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AGRN	NM_198576.4	c.5598C>T	p.Thr1866Thr	synonymous_variant	33/36	ENST00000379370.7	NP_940978.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AGRN	ENST00000379370.7	c.5598C>T	p.Thr1866Thr	synonymous_variant	33/36	1	NM_198576.4	ENSP00000368678.2
AGRN	ENST00000651234.1	c.5295C>T	p.Thr1765Thr	synonymous_variant	33/38			ENSP00000499046.1
AGRN	ENST00000652369.1	c.5283C>T	p.Thr1761Thr	synonymous_variant	32/35			ENSP00000498543.1
AGRN	ENST00000620552.4	c.5196C>T	p.Thr1732Thr	synonymous_variant	34/39	5		ENSP00000484607.1

Frequencies

GnomAD3 genomes AF: 0.00683 AC: 1039 AN: 152232 Hom.: 5 Cov.: 34

Gnomad AFR AF: 0.0109

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.00405

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00434

Gnomad FIN AF: 0.000658

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00691

Gnomad OTH AF: 0.00813

GnomAD3 exomes AF: 0.00493 AC: 1235 AN: 250732 Hom.: 2 AF XY: 0.00481 AC XY: 654 AN XY: 135826

Gnomad AFR exome AF: 0.0109

Gnomad AMR exome AF: 0.00281

Gnomad ASJ exome AF: 0.000498

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00225

Gnomad FIN exome AF: 0.00120

Gnomad NFE exome AF: 0.00736

Gnomad OTH exome AF: 0.00474

GnomAD4 exome AF: 0.00583 AC: 8527 AN: 1461542 Hom.: 28 Cov.: 85 AF XY: 0.00574 AC XY: 4177 AN XY: 727082

Gnomad4 AFR exome AF: 0.0111

Gnomad4 AMR exome AF: 0.00309

Gnomad4 ASJ exome AF: 0.000804

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00299

Gnomad4 FIN exome AF: 0.00132

Gnomad4 NFE exome AF: 0.00659

Gnomad4 OTH exome AF: 0.00508

GnomAD4 genome AF: 0.00685 AC: 1044 AN: 152350 Hom.: 5 Cov.: 34 AF XY: 0.00656 AC XY: 489 AN XY: 74502

Gnomad4 AFR AF: 0.0110

Gnomad4 AMR AF: 0.00405

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00435

Gnomad4 FIN AF: 0.000658

Gnomad4 NFE AF: 0.00691

Gnomad4 OTH AF: 0.00804

Alfa AF: 0.00665 Hom.: 1

Bravo AF: 0.00728

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.00894

EpiControl AF: 0.00913

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

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	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 09, 2018	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	Mar 22, 2021	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2024	AGRN: BP4, BP7, BS1, BS2 -

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	-0.82
CADD	Benign	0.017
DANN	Benign	0.72

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: rs17778478; hg19: chr1-987142; COSMIC: COSV65070088; COSMIC: COSV65070088;