rs138288952

Variant names:

• chr1-1043382-G-A
• rs138288952
• NM_198576.4:c.1528G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_198576.4(AGRN):​c.1528G>A​(p.Gly510Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0103 in 1,609,070 control chromosomes in the GnomAD database, including 105 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0081 (10 hom., cov: 33)
  • Exomes 𝑓: 0.011 (95 hom.)
• Consequence: AGRN NM_198576.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 3.61
• Publications: 10 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012149155).
• BP6: Variant 1-1043382-G-A is Benign according to our data. Variant chr1-1043382-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 263163.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00811 (1236/152322) while in subpopulation NFE AF = 0.0134 (908/68014). AF 95% confidence interval is 0.0126. There are 10 homozygotes in GnomAd4. There are 599 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 10 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.1528G>A	p.Gly510Ser	missense	Exon 8 of 36	NP_940978.2
	AGRN	NM_001305275.2		c.1528G>A	p.Gly510Ser	missense	Exon 8 of 39	NP_001292204.1	O00468-1
	AGRN	NM_001364727.2		c.1213G>A	p.Gly405Ser	missense	Exon 7 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.1528G>A	p.Gly510Ser	missense	Exon 8 of 36	ENSP00000368678.2	O00468-6
	AGRN	ENST00000651234.1		c.1213G>A	p.Gly405Ser	missense	Exon 7 of 38	ENSP00000499046.1	A0A494C1I6
	AGRN	ENST00000652369.2		c.1213G>A	p.Gly405Ser	missense	Exon 7 of 35	ENSP00000498543.1	A0A494C0G5

Frequencies

GnomAD3 genomes AF: 0.00812 AC: 1236 AN: 152204 Hom.: 10 Cov.: 33

Gnomad AFR AF: 0.00212

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00713

Gnomad ASJ AF: 0.00749

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.00715

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0133

Gnomad OTH AF: 0.00812

GnomAD2 exomes AF: 0.00767 AC: 1824 AN: 237686 AF XY: 0.00758

Gnomad AFR exome AF: 0.00173

Gnomad AMR exome AF: 0.00557

Gnomad ASJ exome AF: 0.00873

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00831

Gnomad NFE exome AF: 0.0117

Gnomad OTH exome AF: 0.0102

GnomAD4 exome AF: 0.0105 AC: 15353 AN: 1456748 Hom.: 95 Cov.: 35 AF XY: 0.0103 AC XY: 7468 AN XY: 724508

African (AFR) AF: 0.00152 AC: 51 AN: 33452

American (AMR) AF: 0.00544 AC: 239 AN: 43964

Ashkenazi Jewish (ASJ) AF: 0.00920 AC: 239 AN: 25972

East Asian (EAS) AF: 0.00 AC: 0 AN: 39508

South Asian (SAS) AF: 0.00177 AC: 152 AN: 85666

European-Finnish (FIN) AF: 0.00852 AC: 441 AN: 51744

Middle Eastern (MID) AF: 0.00590 AC: 34 AN: 5758

European-Non Finnish (NFE) AF: 0.0124 AC: 13719 AN: 1110476

Other (OTH) AF: 0.00794 AC: 478 AN: 60208

GnomAD4 genome AF: 0.00811 AC: 1236 AN: 152322 Hom.: 10 Cov.: 33 AF XY: 0.00804 AC XY: 599 AN XY: 74480

African (AFR) AF: 0.00212 AC: 88 AN: 41570

American (AMR) AF: 0.00712 AC: 109 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00749 AC: 26 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00228 AC: 11 AN: 4824

European-Finnish (FIN) AF: 0.00715 AC: 76 AN: 10630

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

European-Non Finnish (NFE) AF: 0.0134 AC: 908 AN: 68014

Other (OTH) AF: 0.00803 AC: 17 AN: 2116

Alfa AF: 0.0113 Hom.: 41

Bravo AF: 0.00742

TwinsUK AF: 0.00728 AC: 27

ALSPAC AF: 0.0109 AC: 42

ESP6500AA AF: 0.00250 AC: 11

ESP6500EA AF: 0.0126 AC: 108

ExAC AF: 0.00703 AC: 849

Asia WGS AF: 0.000866 AC: 3 AN: 3478

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
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	18
DANN	Uncertain	1.0
Eigen	Uncertain	0.19
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.76	T
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	0.33	N
PhyloP100		3.6
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.20
Sift	Benign	0.24	T
Sift4G	Benign	0.28	T
Vest4		0.36
MVP		0.70
MPC		0.55
ClinPred		0.025	T
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
gMVP		0.46
Mutation Taster		=73/27	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: rs138288952; hg19: chr1-978762; COSMIC: COSV65069038; COSMIC: COSV65069038;