1-1041976-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_198576.4(AGRN):c.1198C>T(p.Arg400Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000261 in 1,611,772 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R400Q) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00098 ( 0 hom., cov: 34)

Exomes 𝑓: 0.00019 ( 3 hom. )

Consequence

AGRN
NM_198576.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:4

Conservation

PhyloP100: 0.489

Publications

4 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 -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.01354447).

BP6

Variant 1-1041976-C-T is Benign according to our data. Variant chr1-1041976-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 474098.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAdExome4 at 3 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGRN	NM_198576.4 link	c.1198C>T	p.Arg400Trp	missense_variant	Exon 7 of 36	ENST00000379370.7	NP_940978.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
AGRN	ENST00000379370.7 link	c.1198C>T	p.Arg400Trp	missense_variant	Exon 7 of 36	1	NM_198576.4	ENSP00000368678.2
AGRN	ENST00000651234.1 link	c.883C>T	p.Arg295Trp	missense_variant	Exon 6 of 38			ENSP00000499046.1
AGRN	ENST00000652369.2 link	c.883C>T	p.Arg295Trp	missense_variant	Exon 6 of 35			ENSP00000498543.1
AGRN	ENST00000620552.4 link	c.784C>T	p.Arg262Trp	missense_variant	Exon 7 of 39	5		ENSP00000484607.1

Frequencies

GnomAD3 genomes

AF:

0.000979

AC:

149

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00309

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000206

Gnomad OTH

AF:

0.000956

GnomAD2 exomes

AF:

0.000318

AC:

AN:

245578

AF XY:

0.000276

show subpopulations

Gnomad AFR exome

AF:

0.00305

Gnomad AMR exome

AF:

0.000203

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000137

Gnomad OTH exome

AF:

0.000331

GnomAD4 exome

AF:

0.000186

AC:

271

AN:

1459494

Hom.:

Cov.:

AF XY:

0.000185

AC XY:

134

AN XY:

726134

show subpopulations

African (AFR)

AF:

0.00287

AC:

AN:

33448

American (AMR)

AF:

0.000269

AC:

AN:

44692

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26094

East Asian (EAS)

AF:

0.00

AC:

AN:

39686

South Asian (SAS)

AF:

0.000220

AC:

AN:

86244

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51668

Middle Eastern (MID)

AF:

0.00159

AC:

AN:

5664

European-Non Finnish (NFE)

AF:

0.000101

AC:

112

AN:

1111670

Other (OTH)

AF:

0.000381

AC:

AN:

60328

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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:

0.000978

AC:

149

AN:

152278

Hom.:

Cov.:

AF XY:

0.000860

AC XY:

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.00308

AC:

128

AN:

41564

American (AMR)

AF:

0.000261

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5164

South Asian (SAS)

AF:

0.000207

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000206

AC:

AN:

67998

Other (OTH)

AF:

0.000946

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

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:

0.000286

Hom.:

Bravo

AF:

0.00106

ESP6500AA

AF:

0.00273

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000454

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000491

EpiControl

AF:

0.000296

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Congenital myasthenic syndrome 8

Uncertain:2Benign:1

Sep 01, 2020

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 04, 2017

Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The observed variant c.1198C>T (p.Arg400Trp) has a minor allele frequency of 0.0016 and 0.0005 in 1000 Genomes and ExAC databases respectively. The in silico prediction of the variant is benign by MutationTaster2, damaging by SIFT, and probably damaging by PolyPhen2. -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Mar 23, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

not specified

Benign:1

Jul 30, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: AGRN c.1198C>T (p.Arg400Trp) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00026 in 1610860 control chromosomes in the gnomAD database (v4.1 dataset), including 3 homozygotes. The variant was found predominantly within the African or African-American subpopulation at a frequency of 0.003. The observed variant frequency within African or African-American control individuals, together with the presence in homozygotes suggest that the variant might be benign. To our knowledge, no occurrence of c.1198C>T in individuals affected with Congenital Myasthenic Syndrome-8 and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 474098). Based on the evidence outlined above, the variant was classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.34

CADD

Benign

(source)

DANN

Uncertain

1.0

Eigen

Benign

-0.36

Eigen_PC

Benign

-0.57

FATHMM_MKL

Benign

0.11

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Uncertain

0.23

MetaRNN

Benign

0.014

T;T

MetaSVM

Benign

-0.61

MutationAssessor

Uncertain

2.1

M;.

PhyloP100

0.49

PrimateAI

Benign

0.43

PROVEAN

Uncertain

-2.5

N;.

REVEL

Benign

0.25

Sift

Uncertain

0.013

D;.

Sift4G

Uncertain

0.0030

D;D

Vest4

0.22

MVP

0.84

MPC

0.49

ClinPred

0.024

GERP RS

0.23

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

gMVP

0.28

Mutation Taster

=90/10

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