1-1046551-A-G

Position:

• chr1-1046551-A-G

Variant summary

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

The ENST00000379370.7(AGRN):​c.3066A>G​(p.Ser1022=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.892 in 1,610,386 control chromosomes in the GnomAD database, including 647,914 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.80 (51075 hom., cov: 30)
  • Exomes 𝑓: 0.90 (596839 hom.)
• Consequence: AGRN ENST00000379370.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.03

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=-0.97).
• BP6: Variant 1-1046551-A-G is Benign according to our data. Variant chr1-1046551-A-G is described in ClinVar as [Benign]. Clinvar id is 128297.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-1046551-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.03 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.94 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AGRN	NM_198576.4	c.3066A>G	p.Ser1022=	synonymous_variant	18/36	ENST00000379370.7	NP_940978.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AGRN	ENST00000379370.7	c.3066A>G	p.Ser1022=	synonymous_variant	18/36	1	NM_198576.4	ENSP00000368678	P1
AGRN	ENST00000651234.1	c.2751A>G	p.Ser917=	synonymous_variant	17/38			ENSP00000499046
AGRN	ENST00000652369.1	c.2751A>G	p.Ser917=	synonymous_variant	17/35			ENSP00000498543
AGRN	ENST00000620552.4	c.2652A>G	p.Ser884=	synonymous_variant	18/39	5		ENSP00000484607

Frequencies

GnomAD3 genomes AF: 0.802 AC: 121546 AN: 151638 Hom.: 51078 Cov.: 30

Gnomad AFR AF: 0.514

Gnomad AMI AF: 0.986

Gnomad AMR AF: 0.881

Gnomad ASJ AF: 0.893

Gnomad EAS AF: 0.962

Gnomad SAS AF: 0.892

Gnomad FIN AF: 0.936

Gnomad MID AF: 0.851

Gnomad NFE AF: 0.910

Gnomad OTH AF: 0.824

GnomAD3 exomes AF: 0.887 AC: 216630 AN: 244354 Hom.: 97400 AF XY: 0.891 AC XY: 118804 AN XY: 133338

Gnomad AFR exome AF: 0.497

Gnomad AMR exome AF: 0.930

Gnomad ASJ exome AF: 0.888

Gnomad EAS exome AF: 0.968

Gnomad SAS exome AF: 0.888

Gnomad FIN exome AF: 0.932

Gnomad NFE exome AF: 0.906

Gnomad OTH exome AF: 0.884

GnomAD4 exome AF: 0.902 AC: 1315696 AN: 1458630 Hom.: 596839 Cov.: 79 AF XY: 0.902 AC XY: 654709 AN XY: 725646

Gnomad4 AFR exome AF: 0.488

Gnomad4 AMR exome AF: 0.923

Gnomad4 ASJ exome AF: 0.886

Gnomad4 EAS exome AF: 0.967

Gnomad4 SAS exome AF: 0.887

Gnomad4 FIN exome AF: 0.929

Gnomad4 NFE exome AF: 0.913

Gnomad4 OTH exome AF: 0.881

GnomAD4 genome AF: 0.801 AC: 121566 AN: 151756 Hom.: 51075 Cov.: 30 AF XY: 0.805 AC XY: 59735 AN XY: 74236

Gnomad4 AFR AF: 0.513

Gnomad4 AMR AF: 0.881

Gnomad4 ASJ AF: 0.893

Gnomad4 EAS AF: 0.962

Gnomad4 SAS AF: 0.891

Gnomad4 FIN AF: 0.936

Gnomad4 NFE AF: 0.910

Gnomad4 OTH AF: 0.826

Alfa AF: 0.881 Hom.: 18957

Bravo AF: 0.783

Asia WGS AF: 0.903 AC: 3142 AN: 3478

EpiCase AF: 0.902

EpiControl AF: 0.897

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 19, 2016	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	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -

Congenital myasthenic syndrome 8 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.12
DANN	Benign	0.19

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: rs2465128; hg19: chr1-981931; COSMIC: COSV65068047; COSMIC: COSV65068047;