rs144361725

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_198576.4(AGRN):c.2241G>C(p.Gln747His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000145 in 1,609,848 control chromosomes in the GnomAD database, with no homozygous occurrence. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

AGRN
NM_198576.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.42

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: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGRN	NM_198576.4 link	c.2241G>C	p.Gln747His	missense_variant	Exon 12 of 36	ENST00000379370.7	NP_940978.2	O00468-6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
AGRN	ENST00000379370.7 link	c.2241G>C	p.Gln747His	missense_variant	Exon 12 of 36	1	NM_198576.4	ENSP00000368678.2	O00468-6
AGRN	ENST00000651234.1 link	c.1926G>C	p.Gln642His	missense_variant	Exon 11 of 38			ENSP00000499046.1	A0A494C1I6
AGRN	ENST00000652369.2 link	c.1926G>C	p.Gln642His	missense_variant	Exon 11 of 35			ENSP00000498543.1	A0A494C0G5
AGRN	ENST00000620552.4 link	c.1827G>C	p.Gln609His	missense_variant	Exon 12 of 39	5		ENSP00000484607.1	A0A087X208

Frequencies

GnomAD3 genomes

AF:

0.0000920

AC:

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000162

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000456

AC:

AN:

241222

AF XY:

0.0000609

show subpopulations

Gnomad AFR exome

AF:

0.0000655

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000924

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000151

AC:

220

AN:

1457626

Hom.:

Cov.:

AF XY:

0.000143

AC XY:

104

AN XY:

725006

show subpopulations

African (AFR)

AF:

0.0000599

AC:

AN:

33390

American (AMR)

AF:

0.00

AC:

AN:

44362

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26062

East Asian (EAS)

AF:

0.00

AC:

AN:

39494

South Asian (SAS)

AF:

0.00

AC:

AN:

85930

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51846

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5748

European-Non Finnish (NFE)

AF:

0.000194

AC:

215

AN:

1110566

Other (OTH)

AF:

0.0000498

AC:

AN:

60228

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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:

0.0000920

AC:

AN:

152222

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74370

show subpopulations

African (AFR)

AF:

0.0000724

AC:

AN:

41454

American (AMR)

AF:

0.00

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000162

AC:

AN:

68038

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

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:

0.000123

Hom.:

Bravo

AF:

0.000113

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000331

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Aug 01, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.2241G>C (p.Q747H) alteration is located in exon 12 (coding exon 12) of the AGRN gene. This alteration results from a G to C substitution at nucleotide position 2241, causing the glutamine (Q) at amino acid position 747 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Aug 21, 2017

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Congenital myasthenic syndrome 8

Uncertain:1

Mar 04, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 747 of the AGRN protein (p.Gln747His). This variant is present in population databases (rs144361725, gnomAD 0.008%). 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: 541148). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.54

CADD

Benign

(source)

DANN

Uncertain

0.99

Eigen

Benign

0.15

Eigen_PC

Benign

0.077

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.73

T;T

M_CAP

Benign

0.036

MetaRNN

Uncertain

0.56

D;D

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.5

L;.

PhyloP100

1.4

PrimateAI

Uncertain

0.56

PROVEAN

Uncertain

-2.5

N;.

REVEL

Benign

0.17

Sift

Benign

0.15

T;.

Sift4G

Uncertain

0.038

D;D

Vest4

0.60

MutPred

0.64

Loss of disorder (P = 0.099);.;

MVP

0.70

MPC

0.47

ClinPred

0.17

GERP RS

2.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

gMVP

0.54

Mutation Taster

=57/43

polymorphism

(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