rs2799067

Variant names:

• chr1-1050069-G-A
• rs2799067
• NM_198576.4:c.4879+32G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-1050069-G-A
• chr1-1050069-G-C
• chr1-1050069-G-T

Variant summary

Our verdict is Benign. The variant received -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:3
• Conservation: PhyloP100: 0.166
• Publications: 2 publications found

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]

AGRN Gene-Disease associations (from GenCC):

• congenital myasthenic syndrome 8

  Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• presynaptic congenital myasthenic syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• postsynaptic congenital myasthenic syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198576.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGRN	NM_198576.4	MANE Select	c.4879+32G>A		intron	N/A	NP_940978.2
	AGRN	NM_001305275.2		c.4879+32G>A		intron	N/A	NP_001292204.1
	AGRN	NM_001364727.2		c.4564+32G>A		intron	N/A	NP_001351656.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGRN	ENST00000379370.7	TSL:1 MANE Select	c.4879+32G>A		intron	N/A	ENSP00000368678.2
	AGRN	ENST00000651234.1		c.4564+32G>A		intron	N/A	ENSP00000499046.1
	AGRN	ENST00000652369.2		c.4564+32G>A		intron	N/A	ENSP00000498543.1

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

GnomAD2 exomes AF: 0.583 AC: 62411 AN: 107012 AF XY: 0.592

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 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

African (AFR) AF: 0.165 AC: 4016 AN: 24300

American (AMR) AF: 0.454 AC: 14603 AN: 32192

Ashkenazi Jewish (ASJ) AF: 0.522 AC: 11394 AN: 21808

East Asian (EAS) AF: 0.373 AC: 12205 AN: 32700

South Asian (SAS) AF: 0.510 AC: 34851 AN: 68294

European-Finnish (FIN) AF: 0.462 AC: 19637 AN: 42518

Middle Eastern (MID) AF: 0.523 AC: 1792 AN: 3428

European-Non Finnish (NFE) AF: 0.563 AC: 479217 AN: 850546

Other (OTH) AF: 0.504 AC: 23959 AN: 47568

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

African (AFR) AF: 0.334 AC: 6865 AN: 20550

American (AMR) AF: 0.605 AC: 7233 AN: 11954

Ashkenazi Jewish (ASJ) AF: 0.617 AC: 1745 AN: 2828

East Asian (EAS) AF: 0.555 AC: 1815 AN: 3270

South Asian (SAS) AF: 0.629 AC: 2347 AN: 3734

European-Finnish (FIN) AF: 0.588 AC: 4660 AN: 7926

Middle Eastern (MID) AF: 0.625 AC: 160 AN: 256

European-Non Finnish (NFE) AF: 0.624 AC: 34391 AN: 55140

Other (OTH) AF: 0.579 AC: 921 AN: 1590

Alfa AF: 0.426 Hom.: 1562

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Aug 28, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	1.2
DANN	Benign	0.55
PhyloP100		0.17
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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