rs2799067

chr1-1050069-G-Achr1-1050069-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_198576.4(AGRN):c.4879+32G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.538 in 1,231,314 control chromosomes in the GnomAD database, including 167,007 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.56 (13924 hom., cov: 22)
  • Exomes 𝑓: 0.54 (153083 hom.)
• Consequence: AGRN NM_198576.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.166

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 1-1050069-G-A is Benign according to our data. Variant chr1-1050069-G-A is described in ClinVar as [Benign]. Clinvar id is 263192.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.618 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AGRN	NM_198576.4	c.4879+32G>A		intron_variant		ENST00000379370.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AGRN	ENST00000379370.7	c.4879+32G>A		intron_variant		1	NM_198576.4	P1
AGRN	ENST00000620552.4	c.4465+32G>A		intron_variant		5
AGRN	ENST00000651234.1	c.4564+32G>A		intron_variant
AGRN	ENST00000652369.1	c.4564+32G>A		intron_variant

Frequencies

GnomAD3 genomes AF: 0.561 AC: 60552 AN: 107888 Hom.: 13928 Cov.: 22

Gnomad AFR AF: 0.334

Gnomad AMI AF: 0.607

Gnomad AMR AF: 0.605

Gnomad ASJ AF: 0.617

Gnomad EAS AF: 0.554

Gnomad SAS AF: 0.629

Gnomad FIN AF: 0.588

Gnomad MID AF: 0.637

Gnomad NFE AF: 0.624

Gnomad OTH AF: 0.577

GnomAD3 exomes AF: 0.583 AC: 62411 AN: 107012 Hom.: 13104 AF XY: 0.592 AC XY: 34539 AN XY: 58374

Gnomad AFR exome AF: 0.262

Gnomad AMR exome AF: 0.548

Gnomad ASJ exome AF: 0.624

Gnomad EAS exome AF: 0.505

Gnomad SAS exome AF: 0.616

Gnomad FIN exome AF: 0.616

Gnomad NFE exome AF: 0.617

Gnomad OTH exome AF: 0.575

GnomAD4 exome AF: 0.536 AC: 601674 AN: 1123354 Hom.: 153083 Cov.: 19 AF XY: 0.534 AC XY: 298178 AN XY: 558886

Gnomad4 AFR exome AF: 0.165

Gnomad4 AMR exome AF: 0.454

Gnomad4 ASJ exome AF: 0.522

Gnomad4 EAS exome AF: 0.373

Gnomad4 SAS exome AF: 0.510

Gnomad4 FIN exome AF: 0.462

Gnomad4 NFE exome AF: 0.563

Gnomad4 OTH exome AF: 0.504

GnomAD4 genome AF: 0.561 AC: 60569 AN: 107960 Hom.: 13924 Cov.: 22 AF XY: 0.562 AC XY: 29626 AN XY: 52692

Gnomad4 AFR AF: 0.334

Gnomad4 AMR AF: 0.605

Gnomad4 ASJ AF: 0.617

Gnomad4 EAS AF: 0.555

Gnomad4 SAS AF: 0.629

Gnomad4 FIN AF: 0.588

Gnomad4 NFE AF: 0.624

Gnomad4 OTH AF: 0.579

Alfa AF: 0.426 Hom.: 1562

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 28, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
Cadd	Benign	1.2
Dann	Benign	0.55

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: rs2799067; hg19: chr1-985449; COSMIC: COSV65067820; COSMIC: COSV65067820;