rs748076659

Variant names:

• chr1-1050027-C-A
• rs748076659
• NM_198576.4:c.4869C>A

Your query was ambiguous. Multiple possible variants found:

• chr1-1050027-C-A
• chr1-1050027-C-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4 BP6

The NM_198576.4(AGRN):​c.4869C>A​(p.Phe1623Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000267 in 1,533,250 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000014 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000028 (0 hom.)
• Consequence: AGRN NM_198576.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 0.705
• Publications: 0 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=0.28261936).
• BP6: Variant 1-1050027-C-A is Benign according to our data. Variant chr1-1050027-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 282708.

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.4869C>A	p.Phe1623Leu	missense	Exon 27 of 36	NP_940978.2
	AGRN	NM_001305275.2		c.4869C>A	p.Phe1623Leu	missense	Exon 27 of 39	NP_001292204.1	O00468-1
	AGRN	NM_001364727.2		c.4554C>A	p.Phe1518Leu	missense	Exon 26 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.4869C>A	p.Phe1623Leu	missense	Exon 27 of 36	ENSP00000368678.2	O00468-6
	AGRN	ENST00000651234.1		c.4554C>A	p.Phe1518Leu	missense	Exon 26 of 38	ENSP00000499046.1	A0A494C1I6
	AGRN	ENST00000652369.2		c.4554C>A	p.Phe1518Leu	missense	Exon 26 of 35	ENSP00000498543.1	A0A494C0G5

Frequencies

GnomAD3 genomes AF: 0.0000138 AC: 2 AN: 145432 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000259

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: 0.0000150

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000561 AC: 12 AN: 214024 AF XY: 0.0000675

Gnomad AFR exome AF: 0.0000839

Gnomad AMR exome AF: 0.000127

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000431

Gnomad OTH exome AF: 0.000189

GnomAD4 exome AF: 0.0000281 AC: 39 AN: 1387818 Hom.: 0 Cov.: 69 AF XY: 0.0000334 AC XY: 23 AN XY: 689174

African (AFR) AF: 0.000102 AC: 3 AN: 29312

American (AMR) AF: 0.000170 AC: 7 AN: 41242

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23742

East Asian (EAS) AF: 0.00 AC: 0 AN: 34632

South Asian (SAS) AF: 0.0000355 AC: 3 AN: 84418

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44890

Middle Eastern (MID) AF: 0.000753 AC: 4 AN: 5314

European-Non Finnish (NFE) AF: 0.0000187 AC: 20 AN: 1068876

Other (OTH) AF: 0.0000361 AC: 2 AN: 55392

GnomAD4 genome AF: 0.0000138 AC: 2 AN: 145432 Hom.: 0 Cov.: 33 AF XY: 0.0000141 AC XY: 1 AN XY: 70948

African (AFR) AF: 0.0000259 AC: 1 AN: 38672

American (AMR) AF: 0.00 AC: 0 AN: 14844

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3402

East Asian (EAS) AF: 0.00 AC: 0 AN: 4636

South Asian (SAS) AF: 0.00 AC: 0 AN: 4358

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9688

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 310

European-Non Finnish (NFE) AF: 0.0000150 AC: 1 AN: 66582

Other (OTH) AF: 0.00 AC: 0 AN: 2050

Alfa AF: 0.0000566 Hom.: 0

Bravo AF: 0.0000491

ExAC AF: 0.0000425 AC: 5

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Congenital myasthenic syndrome 8 (1)
-	-	1	Inborn genetic diseases (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	15
DANN	Benign	0.42
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.38
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.12	T
M_CAP	Pathogenic	0.32	D
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	-0.91	N
PhyloP100		0.70
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.70	N
REVEL	Benign	0.27
Sift	Benign	0.83	T
Sift4G	Benign	1.0	T
Vest4		0.14
MutPred		0.41		Gain of glycosylation at S1628 (P = 0.1421)
MVP		0.82
MPC		0.14
ClinPred		0.019	T
GERP RS		4.8
gMVP		0.63
Mutation Taster		=75/25	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs748076659; hg19: chr1-985407;