rs147153797

Variant names:

• chr1-1046079-C-T
• rs147153797
• NM_198576.4:c.2796C>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.2796C>T​(p.Asn932Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000411 in 1,614,046 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00035 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00042 (5 hom.)
• Consequence: AGRN NM_198576.4 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.527
• Publications: 1 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=-0.77).
• BP6: Variant 1-1046079-C-T is Benign according to our data. Variant chr1-1046079-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 263177.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.527 with no splicing effect.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000417 (610/1461712) while in subpopulation MID AF = 0.0135 (78/5768). AF 95% confidence interval is 0.0111. There are 5 homozygotes in GnomAdExome4. There are 364 alleles in the male GnomAdExome4 subpopulation. Median coverage is 39. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 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.2796C>T	p.Asn932Asn	synonymous	Exon 16 of 36	NP_940978.2
	AGRN	NM_001305275.2		c.2796C>T	p.Asn932Asn	synonymous	Exon 16 of 39	NP_001292204.1	O00468-1
	AGRN	NM_001364727.2		c.2481C>T	p.Asn827Asn	synonymous	Exon 15 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.2796C>T	p.Asn932Asn	synonymous	Exon 16 of 36	ENSP00000368678.2	O00468-6
	AGRN	ENST00000651234.1		c.2481C>T	p.Asn827Asn	synonymous	Exon 15 of 38	ENSP00000499046.1	A0A494C1I6
	AGRN	ENST00000652369.2		c.2481C>T	p.Asn827Asn	synonymous	Exon 15 of 35	ENSP00000498543.1	A0A494C0G5

Frequencies

GnomAD3 genomes AF: 0.000342 AC: 52 AN: 152216 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000397

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.000550 AC: 138 AN: 250940 AF XY: 0.000677

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000463

Gnomad ASJ exome AF: 0.00239

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000326

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000417 AC: 610 AN: 1461712 Hom.: 5 Cov.: 39 AF XY: 0.000501 AC XY: 364 AN XY: 727138

African (AFR) AF: 0.000119 AC: 4 AN: 33480

American (AMR) AF: 0.000492 AC: 22 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00249 AC: 65 AN: 26136

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39700

South Asian (SAS) AF: 0.00153 AC: 132 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53256

Middle Eastern (MID) AF: 0.0135 AC: 78 AN: 5768

European-Non Finnish (NFE) AF: 0.000232 AC: 258 AN: 1112000

Other (OTH) AF: 0.000795 AC: 48 AN: 60392

GnomAD4 genome AF: 0.000348 AC: 53 AN: 152334 Hom.: 0 Cov.: 33 AF XY: 0.000376 AC XY: 28 AN XY: 74490

African (AFR) AF: 0.0000962 AC: 4 AN: 41584

American (AMR) AF: 0.000261 AC: 4 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5184

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000397 AC: 27 AN: 68008

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.000654 Hom.: 0

Bravo AF: 0.000355

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.000654

EpiControl AF: 0.000711

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	1.8
DANN	Benign	0.42
PhyloP100		0.53
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs147153797; hg19: chr1-981459; COSMIC: COSV109439893; COSMIC: COSV109439893;