rs768527925

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_198576.4(AGRN):c.384C>G(p.His128Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000166 in 1,613,288 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H128R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00017 ( 1 hom. )

Consequence

AGRN
NM_198576.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

Conservation

PhyloP100: 0.783

Publications

1 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: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.020534337).

BP6

Variant 1-1022383-C-G is Benign according to our data. Variant chr1-1022383-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 541203.

BS1

Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.000168 (245/1461050) while in subpopulation AMR AF = 0.00523 (234/44722). AF 95% confidence interval is 0.00468. There are 1 homozygotes in GnomAdExome4. There are 105 alleles in the male GnomAdExome4 subpopulation. Median coverage is 33. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGRN	NM_198576.4 link	c.384C>G	p.His128Gln	missense_variant	Exon 2 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.384C>G	p.His128Gln	missense_variant	Exon 2 of 36	1	NM_198576.4	ENSP00000368678.2		O00468-6
AGRN	ENST00000620552.4 link	c.-31C>G		5_prime_UTR_variant	Exon 2 of 39	5		ENSP00000484607.1		A0A087X208

Frequencies

GnomAD3 genomes

AF:

0.000145

AC:

AN:

152238

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000982

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000857

AC:

215

AN:

250776

AF XY:

0.000656

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.00607

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000327

GnomAD4 exome

AF:

0.000168

AC:

245

AN:

1461050

Hom.:

Cov.:

AF XY:

0.000144

AC XY:

105

AN XY:

726802

show subpopulations

African (AFR)

AF:

0.000119

AC:

AN:

33480

American (AMR)

AF:

0.00523

AC:

234

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52644

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000360

AC:

AN:

1111966

Other (OTH)

AF:

0.0000497

AC:

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.000145

AC:

AN:

152238

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74378

show subpopulations

African (AFR)

AF:

0.000121

AC:

AN:

41456

American (AMR)

AF:

0.000982

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68044

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

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:

0.000217

Hom.:

Bravo

AF:

0.000416

ExAC

AF:

0.000750

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Feb 20, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.384C>G (p.H128Q) alteration is located in exon 2 (coding exon 2) of the AGRN gene. This alteration results from a C to G substitution at nucleotide position 384, causing the histidine (H) at amino acid position 128 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Feb 01, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BS1 -

AGRN-related disorder

Benign:1

Dec 31, 2020

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Congenital myasthenic syndrome 8

Benign:1

Dec 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.77

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.17

CADD

Benign

(source)

DANN

Uncertain

0.99

Eigen

Benign

0.16

Eigen_PC

Benign

0.13

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.82

M_CAP

Benign

0.040

MetaRNN

Benign

0.021

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.1

PhyloP100

0.78

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

-2.3

REVEL

Benign

0.28

Sift

Uncertain

0.0090

Sift4G

Uncertain

0.025

Vest4

0.72

MutPred

0.77

Gain of ubiquitination at K129 (P = 0.0666);

MVP

0.65

MPC

0.81

ClinPred

0.061

GERP RS

2.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

gMVP

0.47

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