rs147990356

Variant names:

• chr1-1050475-C-T
• rs147990356
• NM_198576.4:c.5025C>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.5025C>T​(p.Gly1675Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00774 in 1,612,942 control chromosomes in the GnomAD database, including 71 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0054 (7 hom., cov: 33)
  • Exomes 𝑓: 0.0080 (64 hom.)
• Consequence: AGRN NM_198576.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.523
• Publications: 0 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=-0.6).
• BP6: Variant 1-1050475-C-T is Benign according to our data. Variant chr1-1050475-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 263194.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.523 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00541 (823/152260) while in subpopulation NFE AF = 0.00912 (620/67978). AF 95% confidence interval is 0.00853. There are 7 homozygotes in GnomAd4. There are 377 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 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.5025C>T	p.Gly1675Gly	synonymous	Exon 29 of 36	NP_940978.2
	AGRN	NM_001305275.2		c.5025C>T	p.Gly1675Gly	synonymous	Exon 29 of 39	NP_001292204.1	O00468-1
	AGRN	NM_001364727.2		c.4710C>T	p.Gly1570Gly	synonymous	Exon 28 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.5025C>T	p.Gly1675Gly	synonymous	Exon 29 of 36	ENSP00000368678.2	O00468-6
	AGRN	ENST00000651234.1		c.4710C>T	p.Gly1570Gly	synonymous	Exon 28 of 38	ENSP00000499046.1	A0A494C1I6
	AGRN	ENST00000652369.2		c.4710C>T	p.Gly1570Gly	synonymous	Exon 28 of 35	ENSP00000498543.1	A0A494C0G5

Frequencies

GnomAD3 genomes AF: 0.00542 AC: 824 AN: 152142 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.00157

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00275

Gnomad ASJ AF: 0.00749

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00786

Gnomad FIN AF: 0.00188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00913

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00589 AC: 1460 AN: 248084 AF XY: 0.00648

Gnomad AFR exome AF: 0.00126

Gnomad AMR exome AF: 0.00224

Gnomad ASJ exome AF: 0.00843

Gnomad EAS exome AF: 0.000111

Gnomad FIN exome AF: 0.00242

Gnomad NFE exome AF: 0.00869

Gnomad OTH exome AF: 0.00512

GnomAD4 exome AF: 0.00798 AC: 11654 AN: 1460682 Hom.: 64 Cov.: 34 AF XY: 0.00803 AC XY: 5835 AN XY: 726674

African (AFR) AF: 0.00111 AC: 37 AN: 33476

American (AMR) AF: 0.00248 AC: 111 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.00827 AC: 216 AN: 26104

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39696

South Asian (SAS) AF: 0.00743 AC: 641 AN: 86258

European-Finnish (FIN) AF: 0.00250 AC: 131 AN: 52386

Middle Eastern (MID) AF: 0.00555 AC: 32 AN: 5766

European-Non Finnish (NFE) AF: 0.00902 AC: 10031 AN: 1111922

Other (OTH) AF: 0.00747 AC: 451 AN: 60376

GnomAD4 genome AF: 0.00541 AC: 823 AN: 152260 Hom.: 7 Cov.: 33 AF XY: 0.00506 AC XY: 377 AN XY: 74458

African (AFR) AF: 0.00156 AC: 65 AN: 41552

American (AMR) AF: 0.00274 AC: 42 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00749 AC: 26 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5182

South Asian (SAS) AF: 0.00786 AC: 38 AN: 4832

European-Finnish (FIN) AF: 0.00188 AC: 20 AN: 10622

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

European-Non Finnish (NFE) AF: 0.00912 AC: 620 AN: 67978

Other (OTH) AF: 0.00473 AC: 10 AN: 2112

Alfa AF: 0.00701 Hom.: 2

Bravo AF: 0.00541

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.0103

EpiControl AF: 0.00960

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	2.9
DANN	Benign	0.78
PhyloP100		0.52
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs147990356; hg19: chr1-985855;