rs150132566

Variant names:

• chr1-1046833-G-C
• rs150132566
• NM_198576.4:c.3264G>C

Your query was ambiguous. Multiple possible variants found:

• chr1-1046833-G-C
• chr1-1046833-G-T

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.3264G>C​(p.Leu1088Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00735 in 1,585,702 control chromosomes in the GnomAD database, including 74 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.013 (24 hom., cov: 33)
  • Exomes 𝑓: 0.0068 (50 hom.)
• Consequence: AGRN NM_198576.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -3.22
• Publications: 9 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=0.0029761791).
• BP6: Variant 1-1046833-G-C is Benign according to our data. Variant chr1-1046833-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 128298.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0128 (1954/152294) while in subpopulation AFR AF = 0.0309 (1285/41558). AF 95% confidence interval is 0.0295. There are 24 homozygotes in GnomAd4. There are 894 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 24 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.3264G>C	p.Leu1088Phe	missense	Exon 19 of 36	NP_940978.2
	AGRN	NM_001305275.2		c.3264G>C	p.Leu1088Phe	missense	Exon 19 of 39	NP_001292204.1	O00468-1
	AGRN	NM_001364727.2		c.2949G>C	p.Leu983Phe	missense	Exon 18 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.3264G>C	p.Leu1088Phe	missense	Exon 19 of 36	ENSP00000368678.2	O00468-6
	AGRN	ENST00000651234.1		c.2949G>C	p.Leu983Phe	missense	Exon 18 of 38	ENSP00000499046.1	A0A494C1I6
	AGRN	ENST00000652369.2		c.2949G>C	p.Leu983Phe	missense	Exon 18 of 35	ENSP00000498543.1	A0A494C0G5

Frequencies

GnomAD3 genomes AF: 0.0127 AC: 1931 AN: 152176 Hom.: 24 Cov.: 33

Gnomad AFR AF: 0.0305

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.00549

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00559

Gnomad FIN AF: 0.000659

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00748

Gnomad OTH AF: 0.0115

GnomAD2 exomes AF: 0.00645 AC: 1299 AN: 201354 AF XY: 0.00597

Gnomad AFR exome AF: 0.0285

Gnomad AMR exome AF: 0.00406

Gnomad ASJ exome AF: 0.00321

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00135

Gnomad NFE exome AF: 0.00769

Gnomad OTH exome AF: 0.00543

GnomAD4 exome AF: 0.00677 AC: 9701 AN: 1433408 Hom.: 50 Cov.: 39 AF XY: 0.00664 AC XY: 4721 AN XY: 710890

African (AFR) AF: 0.0285 AC: 950 AN: 33326

American (AMR) AF: 0.00450 AC: 178 AN: 39540

Ashkenazi Jewish (ASJ) AF: 0.00337 AC: 86 AN: 25512

East Asian (EAS) AF: 0.00 AC: 0 AN: 38854

South Asian (SAS) AF: 0.00349 AC: 289 AN: 82710

European-Finnish (FIN) AF: 0.00134 AC: 63 AN: 47066

Middle Eastern (MID) AF: 0.0199 AC: 114 AN: 5736

European-Non Finnish (NFE) AF: 0.00688 AC: 7578 AN: 1101178

Other (OTH) AF: 0.00745 AC: 443 AN: 59486

GnomAD4 genome AF: 0.0128 AC: 1954 AN: 152294 Hom.: 24 Cov.: 33 AF XY: 0.0120 AC XY: 894 AN XY: 74462

African (AFR) AF: 0.0309 AC: 1285 AN: 41558

American (AMR) AF: 0.00549 AC: 84 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00580 AC: 28 AN: 4828

European-Finnish (FIN) AF: 0.000659 AC: 7 AN: 10622

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.00748 AC: 509 AN: 68008

Other (OTH) AF: 0.0114 AC: 24 AN: 2114

Alfa AF: 0.00533 Hom.: 2

Bravo AF: 0.0141

TwinsUK AF: 0.00458 AC: 17

ALSPAC AF: 0.00675 AC: 26

ESP6500AA AF: 0.0289 AC: 126

ESP6500EA AF: 0.00747 AC: 64

ExAC AF: 0.00616 AC: 735

Asia WGS AF: 0.00722 AC: 25 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	not provided (2)
-	-	1	Congenital myasthenic syndrome 8 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	0.0030
DANN	Benign	0.43
Eigen	Benign	-2.3
Eigen_PC	Benign	-2.4
FATHMM_MKL	Benign	0.0089	N
LIST_S2	Benign	0.073	T
MetaRNN	Benign	0.0030	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.90	L
PhyloP100		-3.2
PrimateAI	Benign	0.39	T
PROVEAN	Benign	0.59	N
REVEL	Benign	0.14
Sift	Benign	0.72	T
Sift4G	Benign	0.73	T
Vest4		0.074
MutPred		0.081		Gain of glycosylation at S1091 (P = 0.1278)
MVP		0.45
MPC		0.13
ClinPred		0.0021	T
GERP RS		-8.4
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.7
gMVP		0.21
Mutation Taster		=99/1	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: rs150132566; hg19: chr1-982213; COSMIC: COSV65067856; COSMIC: COSV65067856;