chr1-1043248-C-T

Variant names:

• chr1-1043248-C-T
• rs116586548
• NM_198576.4:c.1394C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001305275.2(AGRN):​c.1394C>T​(p.Pro465Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000451 in 1,605,312 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P465P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0021 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00028 (3 hom.)
• Consequence: AGRN NM_001305275.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: 0.600
• 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007951736).
• BP6: Variant 1-1043248-C-T is Benign according to our data. Variant chr1-1043248-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 263161.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00211 (321/152238) while in subpopulation AFR AF = 0.00677 (281/41530). AF 95% confidence interval is 0.00612. There are 1 homozygotes in GnomAd4. There are 144 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR,AD gene

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.1394C>T	p.Pro465Leu	missense	Exon 8 of 36	NP_940978.2
	AGRN	NM_001305275.2		c.1394C>T	p.Pro465Leu	missense	Exon 8 of 39	NP_001292204.1
	AGRN	NM_001364727.2		c.1079C>T	p.Pro360Leu	missense	Exon 7 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.1394C>T	p.Pro465Leu	missense	Exon 8 of 36	ENSP00000368678.2
	AGRN	ENST00000651234.1		c.1079C>T	p.Pro360Leu	missense	Exon 7 of 38	ENSP00000499046.1
	AGRN	ENST00000652369.2		c.1079C>T	p.Pro360Leu	missense	Exon 7 of 35	ENSP00000498543.1

Frequencies

GnomAD3 genomes AF: 0.00210 AC: 320 AN: 152118 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00676

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.000959

GnomAD2 exomes AF: 0.000570 AC: 133 AN: 233148 AF XY: 0.000404

Gnomad AFR exome AF: 0.00675

Gnomad AMR exome AF: 0.000676

Gnomad ASJ exome AF: 0.000313

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000570

Gnomad OTH exome AF: 0.000175

GnomAD4 exome AF: 0.000277 AC: 403 AN: 1453074 Hom.: 3 Cov.: 35 AF XY: 0.000278 AC XY: 201 AN XY: 722018

African (AFR) AF: 0.00789 AC: 264 AN: 33448

American (AMR) AF: 0.000696 AC: 30 AN: 43082

Ashkenazi Jewish (ASJ) AF: 0.000271 AC: 7 AN: 25838

East Asian (EAS) AF: 0.0000254 AC: 1 AN: 39312

South Asian (SAS) AF: 0.0000474 AC: 4 AN: 84326

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51944

Middle Eastern (MID) AF: 0.00174 AC: 10 AN: 5756

European-Non Finnish (NFE) AF: 0.0000433 AC: 48 AN: 1109266

Other (OTH) AF: 0.000649 AC: 39 AN: 60102

GnomAD4 genome AF: 0.00211 AC: 321 AN: 152238 Hom.: 1 Cov.: 33 AF XY: 0.00193 AC XY: 144 AN XY: 74444

African (AFR) AF: 0.00677 AC: 281 AN: 41530

American (AMR) AF: 0.00203 AC: 31 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

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

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68012

Other (OTH) AF: 0.000949 AC: 2 AN: 2108

Alfa AF: 0.000687 Hom.: 1

Bravo AF: 0.00221

ESP6500AA AF: 0.00615 AC: 27

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000604 AC: 73

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Congenital myasthenic syndrome 8 (2)
-	-	2	not specified (2)
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	16
DANN	Benign	0.73
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.59
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.90	D
MetaRNN	Benign	0.0080	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L
PhyloP100		0.60
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-4.1	D
REVEL	Benign	0.14
Sift	Benign	0.17	T
Sift4G	Benign	0.10	T
Vest4		0.26
MVP		0.74
MPC		1.0
ClinPred		0.030	T
GERP RS		2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
gMVP		0.54
Mutation Taster		=94/6	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: rs116586548; hg19: chr1-978628; COSMIC: COSV106533025; COSMIC: COSV106533025;