rs199680125

Positions:

chr1-1048186-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM2BP4_StrongBP6_Very_StrongBS1

The NM_198576.4(AGRN):c.3926G>A(p.Arg1309Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000244 in 1,569,432 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0013 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00013 ( 0 hom. )

Consequence

AGRN
NM_198576.4 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 1.24

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.007351905).

BP6

Variant 1-1048186-G-A is Benign according to our data. Variant chr1-1048186-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 474128.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 = 0.00135 (205/152044) while in subpopulation AFR AF= 0.00478 (198/41462). AF 95% confidence interval is 0.00423. There are 1 homozygotes in gnomad4. There are 98 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AGRN	NM_198576.4 linkuse as main transcript	c.3926G>A	p.Arg1309Gln	missense_variant	23/36	ENST00000379370.7	NP_940978.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AGRN	ENST00000379370.7 linkuse as main transcript	c.3926G>A	p.Arg1309Gln	missense_variant	23/36	1	NM_198576.4	ENSP00000368678	P1	O00468-6
AGRN	ENST00000651234.1 linkuse as main transcript	c.3611G>A	p.Arg1204Gln	missense_variant	22/38			ENSP00000499046
AGRN	ENST00000652369.1 linkuse as main transcript	c.3611G>A	p.Arg1204Gln	missense_variant	22/35			ENSP00000498543
AGRN	ENST00000620552.4 linkuse as main transcript	c.3512G>A	p.Arg1171Gln	missense_variant	23/39	5		ENSP00000484607

Frequencies

GnomAD3 genomes

AF:

0.00135

AC:

205

AN:

151932

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00479

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000944

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000958

GnomAD3 exomes

AF:

0.000374

AC:

AN:

174004

Hom.:

AF XY:

0.000316

AC XY:

AN XY:

94884

show subpopulations

Gnomad AFR exome

AF:

0.00551

Gnomad AMR exome

AF:

0.000202

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000720

Gnomad SAS exome

AF:

0.0000810

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000126

AC:

178

AN:

1417388

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

702078

show subpopulations

Gnomad4 AFR exome

AF:

0.00397

Gnomad4 AMR exome

AF:

0.000219

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000805

Gnomad4 SAS exome

AF:

0.0000368

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000165

Gnomad4 OTH exome

AF:

0.000272

GnomAD4 genome

AF:

0.00135

AC:

205

AN:

152044

Hom.:

Cov.:

AF XY:

0.00132

AC XY:

AN XY:

74324

show subpopulations

Gnomad4 AFR

AF:

0.00478

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000944

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000948

Alfa

AF:

0.000268

Hom.:

Bravo

AF:

0.00149

ESP6500AA

AF:

0.00307

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000330

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3476

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 07, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 29, 2020

See Variant Classification Assertion Criteria. -

Congenital myasthenic syndrome 8

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.46

CADD

Benign

DANN

Benign

0.96

Eigen

Benign

-0.99

Eigen_PC

Benign

-0.96

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.71

T;T

MetaRNN

Benign

0.0074

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.94

L;.

MutationTaster

Benign

1.0

PrimateAI

Benign

0.41

PROVEAN

Benign

-1.0

N;.

REVEL

Benign

0.048

Sift

Benign

0.22

T;.

Sift4G

Benign

0.20

T;T

Vest4

0.14

MVP

0.73

MPC

0.14

ClinPred

0.0072

GERP RS

2.4

gMVP

0.31

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over