chr1-1020217-G-T

Position:

• chr1-1020217-G-T

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.45G>T​(p.Pro15=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.331 in 1,393,132 control chromosomes in the GnomAD database, including 77,454 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.31 (7500 hom., cov: 32)
  • Exomes 𝑓: 0.33 (69954 hom.)
• Consequence: AGRN NM_198576.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.853

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=-0.57).
• BP6: Variant 1-1020217-G-T is Benign according to our data. Variant chr1-1020217-G-T is described in ClinVar as [Benign]. Clinvar id is 128310.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-1020217-G-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.853 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.337 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AGRN	NM_198576.4	c.45G>T	p.Pro15=	synonymous_variant	1/36	ENST00000379370.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AGRN	ENST00000379370.7	c.45G>T	p.Pro15=	synonymous_variant	1/36	1	NM_198576.4	P1
AGRN	ENST00000620552.4	c.-370G>T		5_prime_UTR_variant	1/39	5

Frequencies

GnomAD3 genomes AF: 0.307 AC: 46469 AN: 151260 Hom.: 7503 Cov.: 32

Gnomad AFR AF: 0.263

Gnomad AMI AF: 0.392

Gnomad AMR AF: 0.234

Gnomad ASJ AF: 0.282

Gnomad EAS AF: 0.177

Gnomad SAS AF: 0.319

Gnomad FIN AF: 0.435

Gnomad MID AF: 0.296

Gnomad NFE AF: 0.341

Gnomad OTH AF: 0.296

GnomAD3 exomes AF: 0.343 AC: 17342 AN: 50582 Hom.: 3026 AF XY: 0.344 AC XY: 10482 AN XY: 30440

Gnomad AFR exome AF: 0.317

Gnomad AMR exome AF: 0.257

Gnomad ASJ exome AF: 0.332

Gnomad EAS exome AF: 0.235

Gnomad SAS exome AF: 0.337

Gnomad FIN exome AF: 0.448

Gnomad NFE exome AF: 0.366

Gnomad OTH exome AF: 0.354

GnomAD4 exome AF: 0.333 AC: 413987 AN: 1241764 Hom.: 69954 Cov.: 33 AF XY: 0.334 AC XY: 203698 AN XY: 610058

Gnomad4 AFR exome AF: 0.264

Gnomad4 AMR exome AF: 0.246

Gnomad4 ASJ exome AF: 0.296

Gnomad4 EAS exome AF: 0.172

Gnomad4 SAS exome AF: 0.327

Gnomad4 FIN exome AF: 0.420

Gnomad4 NFE exome AF: 0.341

Gnomad4 OTH exome AF: 0.315

GnomAD4 genome AF: 0.307 AC: 46464 AN: 151368 Hom.: 7500 Cov.: 32 AF XY: 0.309 AC XY: 22903 AN XY: 74004

Gnomad4 AFR AF: 0.262

Gnomad4 AMR AF: 0.233

Gnomad4 ASJ AF: 0.282

Gnomad4 EAS AF: 0.177

Gnomad4 SAS AF: 0.319

Gnomad4 FIN AF: 0.435

Gnomad4 NFE AF: 0.341

Gnomad4 OTH AF: 0.295

Alfa AF: 0.319 Hom.: 971

Bravo AF: 0.289

Asia WGS AF: 0.241 AC: 819 AN: 3400

ClinVar

Significance: 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	Genetic Services Laboratory, University of Chicago	Aug 29, 2014	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 04, 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	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -

not provided Benign:1

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	-0.57
CADD	Benign	11
DANN	Benign	0.74
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.4

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

LitVar

Other links and lift over

dbSNP: rs115173026; hg19: chr1-955597;