rs2799068

Positions:

• chr1-1049690-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The ENST00000379370.7(AGRN):​c.4639G>A​(p.Glu1547Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00374 in 1,573,394 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0028 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0038 (21 hom.)
• Consequence: AGRN ENST00000379370.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:4
• Conservation: PhyloP100: 2.14

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]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP6: Variant 1-1049690-G-A is Benign according to our data. Variant chr1-1049690-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 252808.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=3}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00275 (419/152350) while in subpopulation NFE AF= 0.00519 (353/68024). AF 95% confidence interval is 0.00474. There are 2 homozygotes in gnomad4. There are 184 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AGRN	NM_198576.4	c.4639G>A	p.Glu1547Lys	missense_variant	26/36	ENST00000379370.7	NP_940978.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AGRN	ENST00000379370.7	c.4639G>A	p.Glu1547Lys	missense_variant	26/36	1	NM_198576.4	ENSP00000368678	P1
AGRN	ENST00000651234.1	c.4324G>A	p.Glu1442Lys	missense_variant	25/38			ENSP00000499046
AGRN	ENST00000652369.1	c.4324G>A	p.Glu1442Lys	missense_variant	25/35			ENSP00000498543
AGRN	ENST00000620552.4	c.4225G>A	p.Glu1409Lys	missense_variant	26/39	5		ENSP00000484607

Frequencies

GnomAD3 genomes AF: 0.00275 AC: 419 AN: 152232 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000676

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00216

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00519

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00276 AC: 482 AN: 174594 Hom.: 1 AF XY: 0.00253 AC XY: 241 AN XY: 95206

Gnomad AFR exome AF: 0.000641

Gnomad AMR exome AF: 0.00130

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000398

Gnomad FIN exome AF: 0.00263

Gnomad NFE exome AF: 0.00549

Gnomad OTH exome AF: 0.00108

GnomAD4 exome AF: 0.00384 AC: 5458 AN: 1421044 Hom.: 21 Cov.: 46 AF XY: 0.00374 AC XY: 2632 AN XY: 703486

Gnomad4 AFR exome AF: 0.000672

Gnomad4 AMR exome AF: 0.00122

Gnomad4 ASJ exome AF: 0.0000394

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000489

Gnomad4 FIN exome AF: 0.00245

Gnomad4 NFE exome AF: 0.00469

Gnomad4 OTH exome AF: 0.00229

GnomAD4 genome AF: 0.00275 AC: 419 AN: 152350 Hom.: 2 Cov.: 32 AF XY: 0.00247 AC XY: 184 AN XY: 74500

Gnomad4 AFR AF: 0.000674

Gnomad4 AMR AF: 0.000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00216

Gnomad4 NFE AF: 0.00519

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00374 Hom.: 0

Bravo AF: 0.00259

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00389 AC: 15

ESP6500AA AF: 0.000468 AC: 2

ESP6500EA AF: 0.00405 AC: 34

ExAC AF: 0.00226 AC: 264

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Aug 17, 2023	BS1 -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	AGRN: BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 05, 2020	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24791904) -

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Sep 18, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 21, 2015	- -

AGRN-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 24, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Congenital myasthenic syndrome 8 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	21
DANN	Uncertain	1.0
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.42
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Pathogenic	0.29	D
MetaRNN	Benign	0.011	T;T
MetaSVM	Benign	-0.75	T
MutationAssessor	Uncertain	2.6	M;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-3.0	D;.
REVEL	Benign	0.27
Sift	Benign	0.059	T;.
Sift4G	Uncertain	0.053	T;T
Vest4		0.33
MVP		0.80
MPC		0.14
ClinPred		0.044	T
GERP RS		0.29
gMVP		0.78

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.25		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.25		Position offset: -3

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

Publications

LitVar

Other links and lift over

dbSNP: rs2799068; hg19: chr1-985070;