Genetic Variant NM_198576.4:c.4879+41delG (chr1-1050063-AG-A) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_ModerateBA1

The NM_198576.4(AGRN):c.4879+41delG variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.55 ( 19481 hom., cov: 0)

Exomes 𝑓: 0.51 ( 89166 hom. )

Consequence

AGRN
NM_198576.4 intron

Scores

Not classified

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.0280

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: DEFINITIVE, STRONG Submitted by: ClinGen, 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 -10 ACMG points.

BP6

Variant 1-1050063-AG-A is Benign according to our data. Variant chr1-1050063-AG-A is described in ClinVar as Benign. ClinVar VariationId is 1292619.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.723 is higher than 0.05.

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	UniProt
AGRN	NM_198576.4	MANE Select	c.4879+41delG	intron	N/A	NP_940978.2
AGRN	NM_001305275.2		c.4879+41delG	intron	N/A	NP_001292204.1	O00468-1
AGRN	NM_001364727.2		c.4564+41delG	intron	N/A	NP_001351656.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
AGRN	ENST00000379370.7	TSL:1 MANE Select	c.4879+27delG	intron	N/A	ENSP00000368678.2	O00468-6
AGRN	ENST00000651234.1		c.4564+27delG	intron	N/A	ENSP00000499046.1	A0A494C1I6
AGRN	ENST00000652369.2		c.4564+27delG	intron	N/A	ENSP00000498543.1	A0A494C0G5

Frequencies

GnomAD3 genomes

AF:

0.547

AC:

73117

AN:

133630

Hom.:

19472

Cov.:

show subpopulations

Gnomad AFR

AF:

0.731

Gnomad AMI

AF:

0.461

Gnomad AMR

AF:

0.496

Gnomad ASJ

AF:

0.469

Gnomad EAS

AF:

0.649

Gnomad SAS

AF:

0.486

Gnomad FIN

AF:

0.541

Gnomad MID

AF:

0.434

Gnomad NFE

AF:

0.453

Gnomad OTH

AF:

0.524

GnomAD2 exomes

AF:

0.514

AC:

61852

AN:

120388

AF XY:

0.508

show subpopulations

Gnomad AFR exome

AF:

0.742

Gnomad AMR exome

AF:

0.531

Gnomad ASJ exome

AF:

0.479

Gnomad EAS exome

AF:

0.648

Gnomad FIN exome

AF:

0.546

Gnomad NFE exome

AF:

0.455

Gnomad OTH exome

AF:

0.500

GnomAD4 exome

AF:

0.514

AC:

452046

AN:

879708

Hom.:

89166

Cov.:

AF XY:

0.511

AC XY:

227643

AN XY:

445152

show subpopulations

African (AFR)

AF:

0.723

AC:

16315

AN:

22578

American (AMR)

AF:

0.520

AC:

16155

AN:

31072

Ashkenazi Jewish (ASJ)

AF:

0.488

AC:

9451

AN:

19386

East Asian (EAS)

AF:

0.636

AC:

20151

AN:

31674

South Asian (SAS)

AF:

0.472

AC:

31140

AN:

66012

European-Finnish (FIN)

AF:

0.528

AC:

21351

AN:

40474

Middle Eastern (MID)

AF:

0.482

AC:

1371

AN:

2842

European-Non Finnish (NFE)

AF:

0.504

AC:

315265

AN:

626070

Other (OTH)

AF:

0.526

AC:

20847

AN:

39600

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

10786

21572

32357

43143

53929

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9198

18396

27594

36792

45990

<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:

0.547

AC:

73169

AN:

133716

Hom.:

19481

Cov.:

AF XY:

0.548

AC XY:

35845

AN XY:

65382

show subpopulations

African (AFR)

AF:

0.731

AC:

26301

AN:

36004

American (AMR)

AF:

0.496

AC:

7018

AN:

14144

Ashkenazi Jewish (ASJ)

AF:

0.469

AC:

1478

AN:

3152

East Asian (EAS)

AF:

0.649

AC:

2865

AN:

4416

South Asian (SAS)

AF:

0.486

AC:

1975

AN:

4066

European-Finnish (FIN)

AF:

0.541

AC:

4867

AN:

9000

Middle Eastern (MID)

AF:

0.432

AC:

121

AN:

280

European-Non Finnish (NFE)

AF:

0.453

AC:

27191

AN:

59970

Other (OTH)

AF:

0.522

AC:

994

AN:

1906

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

1502

3004

4507

6009

7511

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

636

1272

1908

2544

3180

<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:

0.259

Hom.:

425

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.028

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over