rs17778478

Variant names:

• chr1-1051762-C-T
• rs17778478
• NM_198576.4:c.5598C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-1051762-C-T
• chr1-1051762-C-A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_198576.4(AGRN):​c.5598C>T​(p.Thr1866Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00593 in 1,613,892 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0069 (5 hom., cov: 34)
  • Exomes 𝑓: 0.0058 (28 hom.)
• Consequence: AGRN NM_198576.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.57
• Publications: 3 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: DEFINITIVE, STRONG Submitted by: ClinGen, 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.003).
• BP6: Variant 1-1051762-C-T is Benign according to our data. Variant chr1-1051762-C-T is described in ClinVar as Benign. ClinVar VariationId is 128316.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.57 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00685 (1044/152350) while in subpopulation AFR AF = 0.011 (457/41586). AF 95% confidence interval is 0.0102. There are 5 homozygotes in GnomAd4. There are 489 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AR,AD gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGRN	NM_198576.4	MANE Select	c.5598C>T	p.Thr1866Thr	synonymous	Exon 33 of 36	NP_940978.2
	AGRN	NM_001305275.2		c.5610C>T	p.Thr1870Thr	synonymous	Exon 34 of 39	NP_001292204.1	O00468-1
	AGRN	NM_001364727.2		c.5295C>T	p.Thr1765Thr	synonymous	Exon 33 of 36	NP_001351656.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGRN	ENST00000379370.7	TSL:1 MANE Select	c.5598C>T	p.Thr1866Thr	synonymous	Exon 33 of 36	ENSP00000368678.2	O00468-6
	AGRN	ENST00000651234.1		c.5295C>T	p.Thr1765Thr	synonymous	Exon 33 of 38	ENSP00000499046.1	A0A494C1I6
	AGRN	ENST00000652369.2		c.5283C>T	p.Thr1761Thr	synonymous	Exon 32 of 35	ENSP00000498543.1	A0A494C0G5

Frequencies

GnomAD3 genomes AF: 0.00683 AC: 1039 AN: 152232 Hom.: 5 Cov.: 34

Gnomad AFR AF: 0.0109

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.00405

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00434

Gnomad FIN AF: 0.000658

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00691

Gnomad OTH AF: 0.00813

GnomAD2 exomes AF: 0.00493 AC: 1235 AN: 250732 AF XY: 0.00481

Gnomad AFR exome AF: 0.0109

Gnomad AMR exome AF: 0.00281

Gnomad ASJ exome AF: 0.000498

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00120

Gnomad NFE exome AF: 0.00736

Gnomad OTH exome AF: 0.00474

GnomAD4 exome AF: 0.00583 AC: 8527 AN: 1461542 Hom.: 28 Cov.: 85 AF XY: 0.00574 AC XY: 4177 AN XY: 727082

African (AFR) AF: 0.0111 AC: 370 AN: 33478

American (AMR) AF: 0.00309 AC: 138 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.000804 AC: 21 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00299 AC: 258 AN: 86256

European-Finnish (FIN) AF: 0.00132 AC: 70 AN: 53150

Middle Eastern (MID) AF: 0.00555 AC: 32 AN: 5768

European-Non Finnish (NFE) AF: 0.00659 AC: 7331 AN: 1111958

Other (OTH) AF: 0.00508 AC: 307 AN: 60386

GnomAD4 genome AF: 0.00685 AC: 1044 AN: 152350 Hom.: 5 Cov.: 34 AF XY: 0.00656 AC XY: 489 AN XY: 74502

African (AFR) AF: 0.0110 AC: 457 AN: 41586

American (AMR) AF: 0.00405 AC: 62 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00435 AC: 21 AN: 4832

European-Finnish (FIN) AF: 0.000658 AC: 7 AN: 10632

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00691 AC: 470 AN: 68018

Other (OTH) AF: 0.00804 AC: 17 AN: 2114

Alfa AF: 0.00665 Hom.: 1

Bravo AF: 0.00728

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.00894

EpiControl AF: 0.00913

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	not provided (2)
-	-	1	Congenital myasthenic syndrome 8 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.017
DANN	Benign	0.72
PhyloP100		-1.6
Mutation Taster		=100/0	polymorphism

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: rs17778478; hg19: chr1-987142; COSMIC: COSV65070088; COSMIC: COSV65070088;