rs147990356

chr1-1050475-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_198576.4(AGRN):c.5025C>T(p.Gly1675=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00774 in 1,612,942 control chromosomes in the GnomAD database, including 71 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0054 (7 hom., cov: 33)
  • Exomes 𝑓: 0.0080 (64 hom.)
• Consequence: AGRN NM_198576.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.523

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 1-1050475-C-T is Benign according to our data. Variant chr1-1050475-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 263194.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.523 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00541 (823/152260) while in subpopulation NFE AF= 0.00912 (620/67978). AF 95% confidence interval is 0.00853. There are 7 homozygotes in gnomad4. There are 377 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AGRN	NM_198576.4	c.5025C>T	p.Gly1675=	synonymous_variant	29/36	ENST00000379370.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AGRN	ENST00000379370.7	c.5025C>T	p.Gly1675=	synonymous_variant	29/36	1	NM_198576.4	P1
AGRN	ENST00000651234.1	c.4710C>T	p.Gly1570=	synonymous_variant	28/38
AGRN	ENST00000652369.1	c.4710C>T	p.Gly1570=	synonymous_variant	28/35
AGRN	ENST00000620552.4	c.4611C>T	p.Gly1537=	synonymous_variant	29/39	5

Frequencies

GnomAD3 genomes AF: 0.00542 AC: 824 AN: 152142 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.00157

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00275

Gnomad ASJ AF: 0.00749

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00786

Gnomad FIN AF: 0.00188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00913

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00589 AC: 1460 AN: 248084 Hom.: 12 AF XY: 0.00648 AC XY: 875 AN XY: 134934

Gnomad AFR exome AF: 0.00126

Gnomad AMR exome AF: 0.00224

Gnomad ASJ exome AF: 0.00843

Gnomad EAS exome AF: 0.000111

Gnomad SAS exome AF: 0.00732

Gnomad FIN exome AF: 0.00242

Gnomad NFE exome AF: 0.00869

Gnomad OTH exome AF: 0.00512

GnomAD4 exome AF: 0.00798 AC: 11654 AN: 1460682 Hom.: 64 Cov.: 34 AF XY: 0.00803 AC XY: 5835 AN XY: 726674

Gnomad4 AFR exome AF: 0.00111

Gnomad4 AMR exome AF: 0.00248

Gnomad4 ASJ exome AF: 0.00827

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.00743

Gnomad4 FIN exome AF: 0.00250

Gnomad4 NFE exome AF: 0.00902

Gnomad4 OTH exome AF: 0.00747

GnomAD4 genome AF: 0.00541 AC: 823 AN: 152260 Hom.: 7 Cov.: 33 AF XY: 0.00506 AC XY: 377 AN XY: 74458

Gnomad4 AFR AF: 0.00156

Gnomad4 AMR AF: 0.00274

Gnomad4 ASJ AF: 0.00749

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00786

Gnomad4 FIN AF: 0.00188

Gnomad4 NFE AF: 0.00912

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00701 Hom.: 2

Bravo AF: 0.00541

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.0103

EpiControl AF: 0.00960

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 21, 2020	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 11, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Congenital myasthenic syndrome 8 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 29, 2021	- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Feb 01, 2024

AGRN: BP4, BP7, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
Cadd	Benign	2.9
Dann	Benign	0.78
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

LitVar

Other links and lift over

dbSNP: rs147990356; hg19: chr1-985855;