Genetic Variant NM_198576.4:c.5C>T (chr1-1020177-C-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_198576.4(AGRN):c.5C>T(p.Ala2Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000338 in 1,183,114 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A2D) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

AGRN
NM_198576.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0910

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3339696).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGRN	NM_198576.4 link	c.5C>T	p.Ala2Val	missense_variant	Exon 1 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.5C>T	p.Ala2Val	missense_variant	Exon 1 of 36	1	NM_198576.4	ENSP00000368678.2		O00468-6
AGRN	ENST00000620552.4 link	c.-410C>T		5_prime_UTR_variant	Exon 1 of 39	5		ENSP00000484607.1		A0A087X208

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000338

AC:

AN:

1183114

Hom.:

Cov.:

AF XY:

0.00000173

AC XY:

AN XY:

578674

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

23296

American (AMR)

AF:

0.00

AC:

AN:

14448

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17094

East Asian (EAS)

AF:

0.00

AC:

AN:

25060

South Asian (SAS)

AF:

0.0000203

AC:

AN:

49140

European-Finnish (FIN)

AF:

0.00

AC:

AN:

27354

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3252

European-Non Finnish (NFE)

AF:

0.00000307

AC:

AN:

976046

Other (OTH)

AF:

0.00

AC:

AN:

47424

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.438

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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Benign

-0.39

CADD

Benign

(source)

DANN

Benign

0.96

Eigen

Benign

-0.95

Eigen_PC

Benign

-0.98

FATHMM_MKL

Benign

0.097

LIST_S2

Benign

0.25

M_CAP

Pathogenic

0.94

MetaRNN

Benign

0.33

MetaSVM

Benign

-0.89

MutationAssessor

Benign

1.1

PhyloP100

0.091

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

-0.63

REVEL

Benign

0.14

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Vest4

0.071

MutPred

0.24

Loss of methylation at R4 (P = 0.0842);

MVP

0.70

MPC

0.43

ClinPred

0.43

GERP RS

1.0

PromoterAI

-0.11

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.3

gMVP

0.27

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over