rs75767981

Variant names:

• chr1-1049389-C-T
• rs75767981
• NM_198576.4:c.4452C>T

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.4452C>T​(p.Thr1484Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0019 in 1,598,830 control chromosomes in the GnomAD database, including 46 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0097 (26 hom., cov: 31)
  • Exomes 𝑓: 0.0011 (20 hom.)
• Consequence: AGRN NM_198576.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -8.59
• 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 (BayesDel_noAF=-0.8).
• BP6: Variant 1-1049389-C-T is Benign according to our data. Variant chr1-1049389-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 128308.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-8.59 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00973 (1480/152136) while in subpopulation AFR AF = 0.034 (1410/41500). AF 95% confidence interval is 0.0325. There are 26 homozygotes in GnomAd4. There are 701 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 26 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.4452C>T	p.Thr1484Thr	synonymous	Exon 25 of 36	NP_940978.2
	AGRN	NM_001305275.2		c.4452C>T	p.Thr1484Thr	synonymous	Exon 25 of 39	NP_001292204.1	O00468-1
	AGRN	NM_001364727.2		c.4137C>T	p.Thr1379Thr	synonymous	Exon 24 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.4452C>T	p.Thr1484Thr	synonymous	Exon 25 of 36	ENSP00000368678.2	O00468-6
	AGRN	ENST00000651234.1		c.4137C>T	p.Thr1379Thr	synonymous	Exon 24 of 38	ENSP00000499046.1	A0A494C1I6
	AGRN	ENST00000652369.2		c.4137C>T	p.Thr1379Thr	synonymous	Exon 24 of 35	ENSP00000498543.1	A0A494C0G5

Frequencies

GnomAD3 genomes AF: 0.00968 AC: 1471 AN: 152018 Hom.: 26 Cov.: 31

Gnomad AFR AF: 0.0339

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00334

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00621

GnomAD2 exomes AF: 0.00265 AC: 629 AN: 237784 AF XY: 0.00194

Gnomad AFR exome AF: 0.0340

Gnomad AMR exome AF: 0.00177

Gnomad ASJ exome AF: 0.000101

Gnomad EAS exome AF: 0.000111

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000898

Gnomad OTH exome AF: 0.00101

GnomAD4 exome AF: 0.00108 AC: 1565 AN: 1446694 Hom.: 20 Cov.: 43 AF XY: 0.000930 AC XY: 670 AN XY: 720134

African (AFR) AF: 0.0361 AC: 1208 AN: 33464

American (AMR) AF: 0.00199 AC: 89 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26120

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39688

South Asian (SAS) AF: 0.000348 AC: 30 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38684

Middle Eastern (MID) AF: 0.00295 AC: 17 AN: 5766

European-Non Finnish (NFE) AF: 0.0000324 AC: 36 AN: 1111740

Other (OTH) AF: 0.00300 AC: 181 AN: 60282

GnomAD4 genome AF: 0.00973 AC: 1480 AN: 152136 Hom.: 26 Cov.: 31 AF XY: 0.00942 AC XY: 701 AN XY: 74390

African (AFR) AF: 0.0340 AC: 1410 AN: 41500

American (AMR) AF: 0.00333 AC: 51 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5150

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000736 AC: 5 AN: 67976

Other (OTH) AF: 0.00614 AC: 13 AN: 2116

Alfa AF: 0.00476 Hom.: 1

Bravo AF: 0.0107

Asia WGS AF: 0.00462 AC: 16 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	Congenital myasthenic syndrome 8 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.019
DANN	Benign	0.43
PhyloP100		-8.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs75767981; hg19: chr1-984769;