chr1-1045393-C-T

Variant names:

• chr1-1045393-C-T
• rs75774767
• NM_198576.4:c.2406C>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.2406C>T​(p.Gly802Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00196 in 1,610,942 control chromosomes in the GnomAD database, including 53 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. G802G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.010 (28 hom., cov: 34)
  • Exomes 𝑓: 0.0011 (25 hom.)
• Consequence: AGRN NM_198576.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -4.60
• 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: 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=-0.75).
• BP6: Variant 1-1045393-C-T is Benign according to our data. Variant chr1-1045393-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 128295.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.6 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0102 (1549/152350) while in subpopulation AFR AF = 0.0353 (1468/41580). AF 95% confidence interval is 0.0338. There are 28 homozygotes in GnomAd4. There are 736 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 28 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.2406C>T	p.Gly802Gly	synonymous	Exon 14 of 36	NP_940978.2
	AGRN	NM_001305275.2		c.2406C>T	p.Gly802Gly	synonymous	Exon 14 of 39	NP_001292204.1	O00468-1
	AGRN	NM_001364727.2		c.2091C>T	p.Gly697Gly	synonymous	Exon 13 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.2406C>T	p.Gly802Gly	synonymous	Exon 14 of 36	ENSP00000368678.2	O00468-6
	AGRN	ENST00000651234.1		c.2091C>T	p.Gly697Gly	synonymous	Exon 13 of 38	ENSP00000499046.1	A0A494C1I6
	AGRN	ENST00000652369.2		c.2091C>T	p.Gly697Gly	synonymous	Exon 13 of 35	ENSP00000498543.1	A0A494C0G5

Frequencies

GnomAD3 genomes AF: 0.0101 AC: 1535 AN: 152232 Hom.: 27 Cov.: 34

Gnomad AFR AF: 0.0351

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00386

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00622

GnomAD2 exomes AF: 0.00276 AC: 667 AN: 241370 AF XY: 0.00209

Gnomad AFR exome AF: 0.0396

Gnomad AMR exome AF: 0.00190

Gnomad ASJ exome AF: 0.000102

Gnomad EAS exome AF: 0.0000561

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000157

Gnomad OTH exome AF: 0.000852

GnomAD4 exome AF: 0.00110 AC: 1611 AN: 1458592 Hom.: 25 Cov.: 34 AF XY: 0.000954 AC XY: 692 AN XY: 725696

African (AFR) AF: 0.0368 AC: 1233 AN: 33466

American (AMR) AF: 0.00206 AC: 92 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26110

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39692

South Asian (SAS) AF: 0.0000928 AC: 8 AN: 86230

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50752

Middle Eastern (MID) AF: 0.00382 AC: 22 AN: 5760

European-Non Finnish (NFE) AF: 0.0000522 AC: 58 AN: 1111698

Other (OTH) AF: 0.00319 AC: 192 AN: 60190

GnomAD4 genome AF: 0.0102 AC: 1549 AN: 152350 Hom.: 28 Cov.: 34 AF XY: 0.00988 AC XY: 736 AN XY: 74498

African (AFR) AF: 0.0353 AC: 1468 AN: 41580

American (AMR) AF: 0.00385 AC: 59 AN: 15312

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68032

Other (OTH) AF: 0.00616 AC: 13 AN: 2112

Alfa AF: 0.00356 Hom.: 4

Bravo AF: 0.0112

Asia WGS AF: 0.00404 AC: 14 AN: 3476

EpiCase AF: 0.000218

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Benign/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	-0.75
CADD	Benign	0.35
DANN	Benign	0.43
PhyloP100		-4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Mutation Taster		=98/2	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: rs75774767; hg19: chr1-980773;