chr1-1045444-G-C

Position:

• chr1-1045444-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_198576.4(AGRN):​c.2457G>C​(p.Gly819=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00703 in 1,612,524 control chromosomes in the GnomAD database, including 176 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.021 (68 hom., cov: 33)
  • Exomes 𝑓: 0.0056 (108 hom.)
• Consequence: AGRN NM_198576.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.188

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=-0.67).
• BP6: Variant 1-1045444-G-C is Benign according to our data. Variant chr1-1045444-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 190974.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-1045444-G-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.188 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0545 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AGRN	NM_198576.4	c.2457G>C	p.Gly819=	synonymous_variant	14/36	ENST00000379370.7	NP_940978.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AGRN	ENST00000379370.7	c.2457G>C	p.Gly819=	synonymous_variant	14/36	1	NM_198576.4	ENSP00000368678	P1

Frequencies

GnomAD3 genomes AF: 0.0205 AC: 3113 AN: 152222 Hom.: 68 Cov.: 33

Gnomad AFR AF: 0.0563

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0106

Gnomad ASJ AF: 0.00374

Gnomad EAS AF: 0.0316

Gnomad SAS AF: 0.00952

Gnomad FIN AF: 0.0190

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00243

Gnomad OTH AF: 0.0129

GnomAD3 exomes AF: 0.0109 AC: 2707 AN: 249244 Hom.: 37 AF XY: 0.0102 AC XY: 1375 AN XY: 135284

Gnomad AFR exome AF: 0.0553

Gnomad AMR exome AF: 0.00565

Gnomad ASJ exome AF: 0.00571

Gnomad EAS exome AF: 0.0269

Gnomad SAS exome AF: 0.00840

Gnomad FIN exome AF: 0.0198

Gnomad NFE exome AF: 0.00300

Gnomad OTH exome AF: 0.00886

GnomAD4 exome AF: 0.00562 AC: 8210 AN: 1460184 Hom.: 108 Cov.: 34 AF XY: 0.00555 AC XY: 4031 AN XY: 726366

Gnomad4 AFR exome AF: 0.0579

Gnomad4 AMR exome AF: 0.00595

Gnomad4 ASJ exome AF: 0.00547

Gnomad4 EAS exome AF: 0.0299

Gnomad4 SAS exome AF: 0.00923

Gnomad4 FIN exome AF: 0.0183

Gnomad4 NFE exome AF: 0.00209

Gnomad4 OTH exome AF: 0.00914

GnomAD4 genome AF: 0.0205 AC: 3126 AN: 152340 Hom.: 68 Cov.: 33 AF XY: 0.0210 AC XY: 1566 AN XY: 74486

Gnomad4 AFR AF: 0.0564

Gnomad4 AMR AF: 0.0106

Gnomad4 ASJ AF: 0.00374

Gnomad4 EAS AF: 0.0315

Gnomad4 SAS AF: 0.00973

Gnomad4 FIN AF: 0.0190

Gnomad4 NFE AF: 0.00243

Gnomad4 OTH AF: 0.0128

Alfa AF: 0.00299 Hom.: 1

Bravo AF: 0.0206

EpiCase AF: 0.00224

EpiControl AF: 0.00261

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Likely benign, criteria provided, single submitter	research	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Sep 28, 2016	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 31, 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. -

Congenital myasthenic syndrome 8 Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not provided Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	2.3
DANN	Benign	0.30
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

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: rs112039851; hg19: chr1-980824; COSMIC: COSV65068120; COSMIC: COSV65068120;