1-1050319-C-T

Variant names:

• chr1-1050319-C-T
• rs145111679
• NM_198576.4:c.4966C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_198576.4(AGRN):​c.4966C>T​(p.Arg1656Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000589 in 1,612,832 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts 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. R1656Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00062 (10 hom.)
• Consequence: AGRN NM_198576.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.728
• Publications: 4 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010233223).
• BP6: Variant 1-1050319-C-T is Benign according to our data. Variant chr1-1050319-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 541181.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000329 (50/152018) while in subpopulation SAS AF = 0.00727 (35/4812). AF 95% confidence interval is 0.00538. There are 0 homozygotes in GnomAd4. There are 33 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 10 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.4966C>T	p.Arg1656Trp	missense	Exon 28 of 36	NP_940978.2
	AGRN	NM_001305275.2		c.4966C>T	p.Arg1656Trp	missense	Exon 28 of 39	NP_001292204.1	O00468-1
	AGRN	NM_001364727.2		c.4651C>T	p.Arg1551Trp	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.4966C>T	p.Arg1656Trp	missense	Exon 28 of 36	ENSP00000368678.2	O00468-6
	AGRN	ENST00000651234.1		c.4651C>T	p.Arg1551Trp	missense	Exon 27 of 38	ENSP00000499046.1	A0A494C1I6
	AGRN	ENST00000652369.2		c.4651C>T	p.Arg1551Trp	missense	Exon 27 of 35	ENSP00000498543.1	A0A494C0G5

Frequencies

GnomAD3 genomes AF: 0.000336 AC: 51 AN: 151900 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000726

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00748

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000177

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00105 AC: 262 AN: 248904 AF XY: 0.00142

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000110

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.000276

Gnomad OTH exome AF: 0.000987

GnomAD4 exome AF: 0.000616 AC: 900 AN: 1460814 Hom.: 10 Cov.: 34 AF XY: 0.000819 AC XY: 595 AN XY: 726718

African (AFR) AF: 0.000149 AC: 5 AN: 33478

American (AMR) AF: 0.0000671 AC: 3 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00767 AC: 662 AN: 86258

European-Finnish (FIN) AF: 0.0000572 AC: 3 AN: 52454

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.000165 AC: 183 AN: 1111946

Other (OTH) AF: 0.000679 AC: 41 AN: 60376

GnomAD4 genome AF: 0.000329 AC: 50 AN: 152018 Hom.: 0 Cov.: 33 AF XY: 0.000444 AC XY: 33 AN XY: 74298

African (AFR) AF: 0.0000724 AC: 3 AN: 41430

American (AMR) AF: 0.00 AC: 0 AN: 15284

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.00727 AC: 35 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

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

European-Non Finnish (NFE) AF: 0.000177 AC: 12 AN: 67944

Other (OTH) AF: 0.00 AC: 0 AN: 2104

Alfa AF: 0.000217 Hom.: 0

Bravo AF: 0.000132

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00117 AC: 142

EpiCase AF: 0.000109

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Likely benign

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	-0.30	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	22
DANN	Uncertain	1.0
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.16	N
LIST_S2	Uncertain	0.95	D
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-0.63	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		0.73
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-2.7	D
REVEL	Uncertain	0.37
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.021	D
Vest4		0.57
MVP		0.83
MPC		0.56
ClinPred		0.092	T
GERP RS		2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.77
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs145111679; hg19: chr1-985699; COSMIC: COSV65072249; COSMIC: COSV65072249;