1-1049046-C-T

Variant names:

• chr1-1049046-C-T
• rs201346452
• NM_198576.4:c.4285C>T

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.4285C>T​(p.Arg1429Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000573 in 1,555,724 control chromosomes in the GnomAD database, including 6 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. R1429H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0030 (2 hom., cov: 25)
  • Exomes 𝑓: 0.00032 (4 hom.)
• Consequence: AGRN NM_198576.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.72
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010492057).
• BP6: Variant 1-1049046-C-T is Benign according to our data. Variant chr1-1049046-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 263183.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 = 0.00303 (446/147304) while in subpopulation AFR AF = 0.0111 (429/38534). AF 95% confidence interval is 0.0103. There are 2 homozygotes in GnomAd4. There are 221 alleles in the male GnomAd4 subpopulation. Median coverage is 25. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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.4285C>T	p.Arg1429Cys	missense	Exon 24 of 36	NP_940978.2
	AGRN	NM_001305275.2		c.4285C>T	p.Arg1429Cys	missense	Exon 24 of 39	NP_001292204.1	O00468-1
	AGRN	NM_001364727.2		c.3970C>T	p.Arg1324Cys	missense	Exon 23 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.4285C>T	p.Arg1429Cys	missense	Exon 24 of 36	ENSP00000368678.2	O00468-6
	AGRN	ENST00000651234.1		c.3970C>T	p.Arg1324Cys	missense	Exon 23 of 38	ENSP00000499046.1	A0A494C1I6
	AGRN	ENST00000652369.2		c.3970C>T	p.Arg1324Cys	missense	Exon 23 of 35	ENSP00000498543.1	A0A494C0G5

Frequencies

GnomAD3 genomes AF: 0.00303 AC: 446 AN: 147200 Hom.: 2 Cov.: 25

Gnomad AFR AF: 0.0112

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000805

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.0000149

Gnomad OTH AF: 0.00148

GnomAD2 exomes AF: 0.000764 AC: 122 AN: 159610 AF XY: 0.000680

Gnomad AFR exome AF: 0.0126

Gnomad AMR exome AF: 0.000608

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000327

Gnomad OTH exome AF: 0.000448

GnomAD4 exome AF: 0.000316 AC: 445 AN: 1408420 Hom.: 4 Cov.: 51 AF XY: 0.000286 AC XY: 199 AN XY: 696264

African (AFR) AF: 0.0111 AC: 355 AN: 31848

American (AMR) AF: 0.000606 AC: 23 AN: 37960

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25200

East Asian (EAS) AF: 0.00 AC: 0 AN: 36932

South Asian (SAS) AF: 0.0000125 AC: 1 AN: 80092

European-Finnish (FIN) AF: 0.0000209 AC: 1 AN: 47880

Middle Eastern (MID) AF: 0.000492 AC: 2 AN: 4068

European-Non Finnish (NFE) AF: 0.0000285 AC: 31 AN: 1086250

Other (OTH) AF: 0.000550 AC: 32 AN: 58190

GnomAD4 genome AF: 0.00303 AC: 446 AN: 147304 Hom.: 2 Cov.: 25 AF XY: 0.00308 AC XY: 221 AN XY: 71844

African (AFR) AF: 0.0111 AC: 429 AN: 38534

American (AMR) AF: 0.000804 AC: 12 AN: 14920

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3452

East Asian (EAS) AF: 0.00 AC: 0 AN: 5014

South Asian (SAS) AF: 0.00 AC: 0 AN: 4694

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10118

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.0000149 AC: 1 AN: 67328

Other (OTH) AF: 0.00147 AC: 3 AN: 2044

Alfa AF: 0.000864 Hom.: 0

Bravo AF: 0.00360

ESP6500AA AF: 0.00782 AC: 33

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000730 AC: 82

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	AGRN-related disorder (1)
-	-	1	Congenital myasthenic syndrome 8 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.25
CADD	Uncertain	24
DANN	Uncertain	1.0
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.16	N
LIST_S2	Pathogenic	0.97	D
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-0.54	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		1.7
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-1.7	N
REVEL	Uncertain	0.30
Sift	Benign	0.11	T
Sift4G	Benign	0.17	T
Vest4		0.40
MVP		0.79
MPC		0.64
ClinPred		0.017	T
GERP RS		2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.75
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs201346452; hg19: chr1-984426; COSMIC: COSV65069335; COSMIC: COSV65069335;