1-1045996-C-T

Variant names:

• chr1-1045996-C-T
• rs199593375
• NM_198576.4:c.2713C>T

Variant summary

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

The NM_198576.4(AGRN):​c.2713C>T​(p.Arg905Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000372 in 1,613,818 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R905G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00039 (0 hom.)
• Consequence: AGRN NM_198576.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 0.679
• 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=0.16431165).

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.2713C>T	p.Arg905Cys	missense	Exon 16 of 36	NP_940978.2
	AGRN	NM_001305275.2		c.2713C>T	p.Arg905Cys	missense	Exon 16 of 39	NP_001292204.1	O00468-1
	AGRN	NM_001364727.2		c.2398C>T	p.Arg800Cys	missense	Exon 15 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.2713C>T	p.Arg905Cys	missense	Exon 16 of 36	ENSP00000368678.2	O00468-6
	AGRN	ENST00000651234.1		c.2398C>T	p.Arg800Cys	missense	Exon 15 of 38	ENSP00000499046.1	A0A494C1I6
	AGRN	ENST00000652369.2		c.2398C>T	p.Arg800Cys	missense	Exon 15 of 35	ENSP00000498543.1	A0A494C0G5

Frequencies

GnomAD3 genomes AF: 0.000237 AC: 36 AN: 152182 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.000470

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000291 AC: 73 AN: 250498 AF XY: 0.000332

Gnomad AFR exome AF: 0.0000618

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.000460

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000386 AC: 564 AN: 1461636 Hom.: 0 Cov.: 39 AF XY: 0.000392 AC XY: 285 AN XY: 727126

African (AFR) AF: 0.0000896 AC: 3 AN: 33480

American (AMR) AF: 0.0000894 AC: 4 AN: 44722

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000429 AC: 37 AN: 86258

European-Finnish (FIN) AF: 0.0000376 AC: 2 AN: 53184

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

European-Non Finnish (NFE) AF: 0.000456 AC: 507 AN: 1112002

Other (OTH) AF: 0.000182 AC: 11 AN: 60390

GnomAD4 genome AF: 0.000237 AC: 36 AN: 152182 Hom.: 0 Cov.: 33 AF XY: 0.000215 AC XY: 16 AN XY: 74328

African (AFR) AF: 0.0000724 AC: 3 AN: 41438

American (AMR) AF: 0.0000655 AC: 1 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000470 AC: 32 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000481 Hom.: 0

Bravo AF: 0.000253

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000354 AC: 43

EpiCase AF: 0.000436

EpiControl AF: 0.000533

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Congenital myasthenic syndrome 8 (2)
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	22
DANN	Uncertain	1.0
Eigen	Benign	-0.0041
Eigen_PC	Benign	-0.099
FATHMM_MKL	Benign	0.50	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Uncertain	0.096	D
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.67	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		0.68
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.22
Sift	Benign	0.055	T
Sift4G	Benign	0.074	T
Vest4		0.21
MVP		0.87
MPC		0.18
ClinPred		0.047	T
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.32
Mutation Taster		=96/4	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: rs199593375; hg19: chr1-981376; COSMIC: COSV101039125; COSMIC: COSV101039125;