dbSNP rs60074964: AGRN:c.1603+10G>A (chr1-1043467-G-A) – ACMG Classification: Benign (-15 pts)

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PP3BP6_Very_StrongBS1BS2

The NM_198576.4(AGRN):c.1603+10G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.001 in 1,596,854 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0053 ( 7 hom., cov: 33)

Exomes 𝑓: 0.00055 ( 4 hom. )

Consequence

AGRN
NM_198576.4 intron

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 2.40

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 -15 ACMG points.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

BP6

Variant 1-1043467-G-A is Benign according to our data. Variant chr1-1043467-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 541192.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00527 (803/152272) while in subpopulation AFR AF = 0.0183 (759/41550). AF 95% confidence interval is 0.0172. There are 7 homozygotes in GnomAd4. There are 363 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 7 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198576.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
AGRN	NM_198576.4	MANE Select	c.1603+10G>A	intron	N/A	NP_940978.2
AGRN	NM_001305275.2		c.1603+10G>A	intron	N/A	NP_001292204.1
AGRN	NM_001364727.2		c.1288+10G>A	intron	N/A	NP_001351656.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
AGRN	ENST00000379370.7	TSL:1 MANE Select	c.1603+10G>A	intron	N/A	ENSP00000368678.2
AGRN	ENST00000651234.1		c.1288+10G>A	intron	N/A	ENSP00000499046.1
AGRN	ENST00000652369.2		c.1288+10G>A	intron	N/A	ENSP00000498543.1

Frequencies

GnomAD3 genomes

AF:

0.00526

AC:

800

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0182

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00196

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:

0.0000882

Gnomad OTH

AF:

0.00383

GnomAD2 exomes

AF:

0.00136

AC:

303

AN:

222730

AF XY:

0.00103

show subpopulations

Gnomad AFR exome

AF:

0.0192

Gnomad AMR exome

AF:

0.000821

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000579

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000401

Gnomad OTH exome

AF:

0.000177

GnomAD4 exome

AF:

0.000553

AC:

799

AN:

1444582

Hom.:

Cov.:

AF XY:

0.000468

AC XY:

336

AN XY:

718578

show subpopulations

African (AFR)

AF:

0.0194

AC:

646

AN:

33378

American (AMR)

AF:

0.00101

AC:

AN:

43386

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25866

East Asian (EAS)

AF:

0.00

AC:

AN:

39222

South Asian (SAS)

AF:

0.0000817

AC:

AN:

85660

European-Finnish (FIN)

AF:

0.0000226

AC:

AN:

44202

Middle Eastern (MID)

AF:

0.00174

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.0000163

AC:

AN:

1107222

Other (OTH)

AF:

0.00122

AC:

AN:

59894

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

105

157

210

262

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

<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:

0.00527

AC:

803

AN:

152272

Hom.:

Cov.:

AF XY:

0.00488

AC XY:

363

AN XY:

74428

show subpopulations

African (AFR)

AF:

0.0183

AC:

759

AN:

41550

American (AMR)

AF:

0.00196

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000882

AC:

AN:

68008

Other (OTH)

AF:

0.00379

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

121

161

201

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00406

Hom.:

Bravo

AF:

0.00579

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Congenital myasthenic syndrome 8 (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.49

CADD

Uncertain

(source)

DANN

Benign

0.58

PhyloP100

2.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.2

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.71

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.71

Position offset: 1

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over