Variant rs749209897 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PM4_Supporting

The NM_198576.4(AGRN):c.596_598del(p.Lys199del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.000914 in 1,544,474 control chromosomes in the GnomAD database, including 4 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00063 ( 0 hom., cov: 29)

Exomes 𝑓: 0.00094 ( 4 hom. )

Consequence

AGRN
NM_198576.4 inframe_deletion

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 4.40

Variant links:

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]

AGRN links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_198576.4. Strenght limited to Supporting due to length of the change: 1aa.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AGRN	NM_198576.4 linkuse as main transcript	c.596_598del	p.Lys199del	inframe_deletion	4/36	ENST00000379370.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AGRN	ENST00000379370.7 linkuse as main transcript	c.596_598del	p.Lys199del	inframe_deletion	4/36	1	NM_198576.4	P1	O00468-6

Frequencies

GnomAD3 genomes

AF:

0.000633

AC:

AN:

151748

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000218

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00122

Gnomad OTH

AF:

0.000481

GnomAD3 exomes

AF:

0.000664

AC:

AN:

144472

Hom.:

AF XY:

0.000615

AC XY:

AN XY:

78108

show subpopulations

Gnomad AFR exome

AF:

0.000400

Gnomad AMR exome

AF:

0.000405

Gnomad ASJ exome

AF:

0.000121

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000949

Gnomad NFE exome

AF:

0.00135

Gnomad OTH exome

AF:

0.00141

GnomAD4 exome

AF:

0.000944

AC:

1315

AN:

1392726

Hom.:

AF XY:

0.000954

AC XY:

656

AN XY:

687378

show subpopulations

Gnomad4 AFR exome

AF:

0.000190

Gnomad4 AMR exome

AF:

0.000390

Gnomad4 ASJ exome

AF:

0.0000795

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000237

Gnomad4 NFE exome

AF:

0.00116

Gnomad4 OTH exome

AF:

0.000674

GnomAD4 genome

AF:

0.000633

AC:

AN:

151748

Hom.:

Cov.:

AF XY:

0.000540

AC XY:

AN XY:

74126

show subpopulations

Gnomad4 AFR

AF:

0.000218

Gnomad4 AMR

AF:

0.000197

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00122

Gnomad4 OTH

AF:

0.000481

Alfa

AF:

0.000868

Hom.:

Bravo

AF:

0.000646

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Congenital myasthenic syndrome 8

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 11, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 13, 2022	This variant, c.596_598del, results in the deletion of 1 amino acid(s) of the AGRN protein (p.Lys199del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs749209897, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with AGRN-related conditions. ClinVar contains an entry for this variant (Variation ID: 474163). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jun 17, 2022

In-frame deletion of 1 amino acids in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over