rs200051701

Variant names:

• chr1-1050277-G-A
• rs200051701
• NM_198576.4:c.4924G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_198576.4(AGRN):​c.4924G>A​(p.Gly1642Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00021 in 1,613,064 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. G1642G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00022 (0 hom.)
• Consequence: AGRN NM_198576.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.20
• Publications: 1 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.24131757).

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.4924G>A	p.Gly1642Ser	missense	Exon 28 of 36	NP_940978.2
	AGRN	NM_001305275.2		c.4924G>A	p.Gly1642Ser	missense	Exon 28 of 39	NP_001292204.1	O00468-1
	AGRN	NM_001364727.2		c.4609G>A	p.Gly1537Ser	missense	Exon 27 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.4924G>A	p.Gly1642Ser	missense	Exon 28 of 36	ENSP00000368678.2	O00468-6
	AGRN	ENST00000651234.1		c.4609G>A	p.Gly1537Ser	missense	Exon 27 of 38	ENSP00000499046.1	A0A494C1I6
	AGRN	ENST00000652369.2		c.4609G>A	p.Gly1537Ser	missense	Exon 27 of 35	ENSP00000498543.1	A0A494C0G5

Frequencies

GnomAD3 genomes AF: 0.0000790 AC: 12 AN: 151982 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000967

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000108 AC: 27 AN: 249770 AF XY: 0.000133

Gnomad AFR exome AF: 0.000125

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000550

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.000195

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000224 AC: 327 AN: 1460964 Hom.: 0 Cov.: 34 AF XY: 0.000228 AC XY: 166 AN XY: 726782

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39698

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86258

European-Finnish (FIN) AF: 0.0000761 AC: 4 AN: 52574

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000276 AC: 307 AN: 1111962

Other (OTH) AF: 0.000116 AC: 7 AN: 60378

GnomAD4 genome AF: 0.0000789 AC: 12 AN: 152100 Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6 AN XY: 74370

African (AFR) AF: 0.0000964 AC: 4 AN: 41478

American (AMR) AF: 0.00 AC: 0 AN: 15296

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

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

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 67958

Other (OTH) AF: 0.00 AC: 0 AN: 2108

Alfa AF: 0.000180 Hom.: 0

Bravo AF: 0.0000529

ExAC AF: 0.0000824 AC: 10

EpiCase AF: 0.000327

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Congenital myasthenic syndrome 8 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	23
DANN	Benign	0.89
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.84	T
M_CAP	Pathogenic	0.49	D
MetaRNN	Benign	0.24	T
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		3.2
PrimateAI	Uncertain	0.52	T
PROVEAN	Pathogenic	-4.6	D
REVEL	Uncertain	0.42
Sift	Uncertain	0.025	D
Sift4G	Benign	0.094	T
Vest4		0.26
MVP		0.81
MPC		0.54
ClinPred		0.22	T
GERP RS		3.1
gMVP		0.74
Mutation Taster		=58/42	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs200051701; hg19: chr1-985657;