rs184970403

Variant names:

• chr1-1048224-C-T
• rs184970403
• NM_198576.4:c.3964C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-1048224-C-T
• chr1-1048224-C-G

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.3964C>T​(p.Arg1322Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00145 in 1,545,014 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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. R1322Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0074 (6 hom., cov: 32)
  • Exomes 𝑓: 0.00080 (13 hom.)
• Consequence: AGRN NM_198576.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.478
• Publications: 3 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=0.004160583).
• BP6: Variant 1-1048224-C-T is Benign according to our data. Variant chr1-1048224-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 128305.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 = 0.0074 (1126/152246) while in subpopulation AFR AF = 0.0256 (1063/41532). AF 95% confidence interval is 0.0243. There are 6 homozygotes in GnomAd4. There are 563 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 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.3964C>T	p.Arg1322Trp	missense	Exon 23 of 36	NP_940978.2
	AGRN	NM_001305275.2		c.3964C>T	p.Arg1322Trp	missense	Exon 23 of 39	NP_001292204.1	O00468-1
	AGRN	NM_001364727.2		c.3649C>T	p.Arg1217Trp	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.3964C>T	p.Arg1322Trp	missense	Exon 23 of 36	ENSP00000368678.2	O00468-6
	AGRN	ENST00000651234.1		c.3649C>T	p.Arg1217Trp	missense	Exon 22 of 38	ENSP00000499046.1	A0A494C1I6
	AGRN	ENST00000652369.2		c.3649C>T	p.Arg1217Trp	missense	Exon 22 of 35	ENSP00000498543.1	A0A494C0G5

Frequencies

GnomAD3 genomes AF: 0.00740 AC: 1126 AN: 152136 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.0256

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00314

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00182 AC: 256 AN: 140956 AF XY: 0.00148

Gnomad AFR exome AF: 0.0307

Gnomad AMR exome AF: 0.00100

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000981

Gnomad OTH exome AF: 0.00123

GnomAD4 exome AF: 0.000804 AC: 1120 AN: 1392768 Hom.: 13 Cov.: 35 AF XY: 0.000676 AC XY: 464 AN XY: 686568

African (AFR) AF: 0.0278 AC: 882 AN: 31752

American (AMR) AF: 0.00137 AC: 50 AN: 36396

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24810

East Asian (EAS) AF: 0.0000555 AC: 2 AN: 36066

South Asian (SAS) AF: 0.000165 AC: 13 AN: 78762

European-Finnish (FIN) AF: 0.0000222 AC: 1 AN: 44950

Middle Eastern (MID) AF: 0.00198 AC: 11 AN: 5564

European-Non Finnish (NFE) AF: 0.0000371 AC: 40 AN: 1076730

Other (OTH) AF: 0.00210 AC: 121 AN: 57738

GnomAD4 genome AF: 0.00740 AC: 1126 AN: 152246 Hom.: 6 Cov.: 32 AF XY: 0.00756 AC XY: 563 AN XY: 74438

African (AFR) AF: 0.0256 AC: 1063 AN: 41532

American (AMR) AF: 0.00307 AC: 47 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68008

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

Alfa AF: 0.00234 Hom.: 2

Bravo AF: 0.00824

ESP6500AA AF: 0.0194 AC: 78

ESP6500EA AF: 0.000126 AC: 1

ExAC AF: 0.00138 AC: 146

Asia WGS AF: 0.00173 AC: 6 AN: 3474

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	1	Congenital myasthenic syndrome 8 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	14
DANN	Uncertain	1.0
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.77	T
MetaRNN	Benign	0.0042	T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	0.90	L
PhyloP100		0.48
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.18
Sift	Benign	0.19	T
Sift4G	Uncertain	0.0080	D
Vest4		0.22
MVP		0.84
MPC		0.13
ClinPred		0.0082	T
GERP RS		0.061
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.34
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: rs184970403; hg19: chr1-983604;