rs749209897

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 1P and 5B. PM4_SupportingBP6BS2

The NM_198576.4(AGRN):c.596_598delAGA(p.Lys199del) variant causes a disruptive 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. K199K) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00063 ( 0 hom., cov: 29)

Exomes 𝑓: 0.00094 ( 4 hom. )

Consequence

AGRN
NM_198576.4 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

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

Conservation

PhyloP100: 4.40

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

congenital myasthenic syndrome 8
Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
presynaptic congenital myasthenic syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
postsynaptic congenital myasthenic syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

AGRN links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

PM4

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

BP6

Variant 1-1040744-CAAG-C is Benign according to our data. Variant chr1-1040744-CAAG-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 474163.

BS2

High Homozygotes in GnomAdExome4 at 4 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGRN	NM_198576.4 link	c.596_598delAGA	p.Lys199del	disruptive_inframe_deletion	Exon 4 of 36	ENST00000379370.7	NP_940978.2	O00468-6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGRN	ENST00000379370.7 link	c.596_598delAGA	p.Lys199del	disruptive_inframe_deletion	Exon 4 of 36	1	NM_198576.4	ENSP00000368678.2		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

GnomAD2 exomes

AF:

0.000664

AC:

AN:

144472

AF XY:

0.000615

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 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

African (AFR)

AF:

0.000190

AC:

AN:

31622

American (AMR)

AF:

0.000390

AC:

AN:

35890

Ashkenazi Jewish (ASJ)

AF:

0.0000795

AC:

AN:

25158

East Asian (EAS)

AF:

0.00

AC:

AN:

35860

South Asian (SAS)

AF:

0.00

AC:

AN:

79284

European-Finnish (FIN)

AF:

0.0000237

AC:

AN:

42208

Middle Eastern (MID)

AF:

0.000184

AC:

AN:

5448

European-Non Finnish (NFE)

AF:

0.00116

AC:

1252

AN:

1079352

Other (OTH)

AF:

0.000674

AC:

AN:

57904

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

173

260

346

433

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

156

208

260

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000633

AC:

AN:

151748

Hom.:

Cov.:

AF XY:

0.000540

AC XY:

AN XY:

74126

show subpopulations

African (AFR)

AF:

0.000218

AC:

AN:

41296

American (AMR)

AF:

0.000197

AC:

AN:

15250

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5118

South Asian (SAS)

AF:

0.00

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10580

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00122

AC:

AN:

67918

Other (OTH)

AF:

0.000481

AC:

AN:

2080

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

Nov 11, 2019

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 13, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Jun 17, 2022

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

PhyloP100

4.4

Mutation Taster

=43/57

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over