chr1-1051538-C-T

Variant names:

• chr1-1051538-C-T
• rs72900459
• NM_198576.4:c.5456C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001305275.2(AGRN):​c.5468C>T​(p.Thr1823Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000791 in 1,567,284 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.00036 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000049 (0 hom.)
• Consequence: AGRN NM_001305275.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.33
• 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: STRONG Submitted by: PanelApp Australia, 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 -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.027648062).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001305275.2. 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.5456C>T	p.Thr1819Ile	missense	Exon 32 of 36	NP_940978.2
	AGRN	NM_001305275.2		c.5468C>T	p.Thr1823Ile	missense	Exon 33 of 39	NP_001292204.1
	AGRN	NM_001364727.2		c.5153C>T	p.Thr1718Ile	missense	Exon 32 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.5456C>T	p.Thr1819Ile	missense	Exon 32 of 36	ENSP00000368678.2
	AGRN	ENST00000651234.1		c.5153C>T	p.Thr1718Ile	missense	Exon 32 of 38	ENSP00000499046.1
	AGRN	ENST00000652369.2		c.5141C>T	p.Thr1714Ile	missense	Exon 31 of 35	ENSP00000498543.1

Frequencies

GnomAD3 genomes AF: 0.000368 AC: 56 AN: 152232 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00133

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000120 AC: 22 AN: 183752 AF XY: 0.0000993

Gnomad AFR exome AF: 0.00155

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000266

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000208

GnomAD4 exome AF: 0.0000488 AC: 69 AN: 1414934 Hom.: 0 Cov.: 85 AF XY: 0.0000558 AC XY: 39 AN XY: 699116

African (AFR) AF: 0.00168 AC: 55 AN: 32772

American (AMR) AF: 0.0000498 AC: 2 AN: 40138

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24644

East Asian (EAS) AF: 0.000209 AC: 8 AN: 38214

South Asian (SAS) AF: 0.00 AC: 0 AN: 80808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45994

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5520

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1088360

Other (OTH) AF: 0.0000684 AC: 4 AN: 58484

GnomAD4 genome AF: 0.000361 AC: 55 AN: 152350 Hom.: 0 Cov.: 34 AF XY: 0.000322 AC XY: 24 AN XY: 74498

African (AFR) AF: 0.00130 AC: 54 AN: 41584

American (AMR) AF: 0.00 AC: 0 AN: 15312

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

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10632

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000837 Hom.: 0

Bravo AF: 0.000476

ESP6500AA AF: 0.00138 AC: 6

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000117 AC: 14

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Congenital myasthenic syndrome 8 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	23
DANN	Uncertain	1.0
Eigen	Uncertain	0.20
Eigen_PC	Benign	0.16
FATHMM_MKL	Benign	0.73	D
LIST_S2	Uncertain	0.88	D
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.028	T
MetaSVM	Uncertain	-0.25	T
PhyloP100		1.3
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-3.3	D
REVEL	Uncertain	0.32
Sift	Benign	0.039	D
Sift4G	Uncertain	0.0020	D
Vest4		0.54
MVP		0.78
MPC		0.58
ClinPred		0.14	T
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
gMVP		0.36
Mutation Taster		=68/32	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs72900459; hg19: chr1-986918;