rs199680125

Variant names:

• chr1-1048186-G-A
• rs199680125
• NM_198576.4:c.3926G>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS1

The NM_198576.4(AGRN):​c.3926G>A​(p.Arg1309Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000244 in 1,569,432 control chromosomes in the GnomAD database, including 1 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. R1309W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0013 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: AGRN NM_198576.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.24
• 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007351905).
• BP6: Variant 1-1048186-G-A is Benign according to our data. Variant chr1-1048186-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 474128.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 = 0.00135 (205/152044) while in subpopulation AFR AF = 0.00478 (198/41462). AF 95% confidence interval is 0.00423. There are 1 homozygotes in GnomAd4. There are 98 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.3926G>A	p.Arg1309Gln	missense	Exon 23 of 36	NP_940978.2
	AGRN	NM_001305275.2		c.3926G>A	p.Arg1309Gln	missense	Exon 23 of 39	NP_001292204.1	O00468-1
	AGRN	NM_001364727.2		c.3611G>A	p.Arg1204Gln	missense	Exon 22 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.3926G>A	p.Arg1309Gln	missense	Exon 23 of 36	ENSP00000368678.2	O00468-6
	AGRN	ENST00000651234.1		c.3611G>A	p.Arg1204Gln	missense	Exon 22 of 38	ENSP00000499046.1	A0A494C1I6
	AGRN	ENST00000652369.2		c.3611G>A	p.Arg1204Gln	missense	Exon 22 of 35	ENSP00000498543.1	A0A494C0G5

Frequencies

GnomAD3 genomes AF: 0.00135 AC: 205 AN: 151932 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00479

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000944

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000958

GnomAD2 exomes AF: 0.000374 AC: 65 AN: 174004 AF XY: 0.000316

Gnomad AFR exome AF: 0.00551

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000720

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000126 AC: 178 AN: 1417388 Hom.: 0 Cov.: 35 AF XY: 0.000108 AC XY: 76 AN XY: 702078

African (AFR) AF: 0.00397 AC: 129 AN: 32494

American (AMR) AF: 0.000219 AC: 9 AN: 41188

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25454

East Asian (EAS) AF: 0.0000805 AC: 3 AN: 37246

South Asian (SAS) AF: 0.0000368 AC: 3 AN: 81502

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40964

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5606

European-Non Finnish (NFE) AF: 0.0000165 AC: 18 AN: 1094082

Other (OTH) AF: 0.000272 AC: 16 AN: 58852

GnomAD4 genome AF: 0.00135 AC: 205 AN: 152044 Hom.: 1 Cov.: 32 AF XY: 0.00132 AC XY: 98 AN XY: 74324

African (AFR) AF: 0.00478 AC: 198 AN: 41462

American (AMR) AF: 0.000262 AC: 4 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00 AC: 0 AN: 4806

European-Finnish (FIN) AF: 0.0000944 AC: 1 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67946

Other (OTH) AF: 0.000948 AC: 2 AN: 2110

Alfa AF: 0.000259 Hom.: 0

Bravo AF: 0.00149

ESP6500AA AF: 0.00307 AC: 13

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000330 AC: 38

Asia WGS AF: 0.000289 AC: 1 AN: 3476

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Congenital myasthenic syndrome 8 (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	14
DANN	Benign	0.96
Eigen	Benign	-0.99
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.71	T
MetaRNN	Benign	0.0074	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.94	L
PhyloP100		1.2
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.048
Sift	Benign	0.22	T
Sift4G	Benign	0.20	T
Vest4		0.14
MVP		0.73
MPC		0.14
ClinPred		0.0072	T
GERP RS		2.4
gMVP		0.31
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs199680125; hg19: chr1-983566;