chr1-1046845-C-T

Variant names:

• chr1-1046845-C-T
• rs201166586
• NM_198576.4:c.3276C>T

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BS1 BS2

The NM_198576.4(AGRN):​c.3276C>T​(p.Ser1092Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000252 in 1,585,974 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00048 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00023 (4 hom.)
• Consequence: AGRN NM_198576.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.885
• Publications: 4 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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 1-1046845-C-T is Benign according to our data. Variant chr1-1046845-C-T is described in ClinVar as Benign. ClinVar VariationId is 474115.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.885 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000479 (73/152294) while in subpopulation EAS AF = 0.0108 (56/5186). AF 95% confidence interval is 0.00854. There are 0 homozygotes in GnomAd4. There are 48 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 4 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGRN	NM_198576.4	MANE Select	c.3276C>T	p.Ser1092Ser	synonymous	Exon 19 of 36	NP_940978.2
	AGRN	NM_001305275.2		c.3276C>T	p.Ser1092Ser	synonymous	Exon 19 of 39	NP_001292204.1
	AGRN	NM_001364727.2		c.2961C>T	p.Ser987Ser	synonymous	Exon 18 of 36	NP_001351656.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGRN	ENST00000379370.7	TSL:1 MANE Select	c.3276C>T	p.Ser1092Ser	synonymous	Exon 19 of 36	ENSP00000368678.2
	AGRN	ENST00000651234.1		c.2961C>T	p.Ser987Ser	synonymous	Exon 18 of 38	ENSP00000499046.1
	AGRN	ENST00000652369.2		c.2961C>T	p.Ser987Ser	synonymous	Exon 18 of 35	ENSP00000498543.1

Frequencies

GnomAD3 genomes AF: 0.000486 AC: 74 AN: 152176 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0110

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.000916 AC: 184 AN: 200874 AF XY: 0.000891

Gnomad AFR exome AF: 0.000163

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0113

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000585

GnomAD4 exome AF: 0.000228 AC: 327 AN: 1433680 Hom.: 4 Cov.: 39 AF XY: 0.000232 AC XY: 165 AN XY: 710912

African (AFR) AF: 0.0000600 AC: 2 AN: 33330

American (AMR) AF: 0.0000253 AC: 1 AN: 39516

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25498

East Asian (EAS) AF: 0.00639 AC: 248 AN: 38794

South Asian (SAS) AF: 0.000327 AC: 27 AN: 82552

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47996

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5734

European-Non Finnish (NFE) AF: 0.00000545 AC: 6 AN: 1100782

Other (OTH) AF: 0.000723 AC: 43 AN: 59478

GnomAD4 genome AF: 0.000479 AC: 73 AN: 152294 Hom.: 0 Cov.: 33 AF XY: 0.000645 AC XY: 48 AN XY: 74474

African (AFR) AF: 0.000217 AC: 9 AN: 41552

American (AMR) AF: 0.0000653 AC: 1 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.0108 AC: 56 AN: 5186

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68006

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

Alfa AF: 0.0000842 Hom.: 0

Bravo AF: 0.000374

Asia WGS AF: 0.00693 AC: 24 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Congenital myasthenic syndrome 8 Benign:1

Jan 22, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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	-0.74
CADD	Benign	1.5
DANN	Benign	0.72
PhyloP100		-0.89
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.1
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: rs201166586; hg19: chr1-982225; COSMIC: COSV107482018; COSMIC: COSV107482018;