rs17160775

Positions:

• chr1-1050446-G-A
• chr1-1050446-G-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_198576.4(AGRN):​c.4996G>A​(p.Val1666Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00816 in 1,612,926 control chromosomes in the GnomAD database, including 928 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1666F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.044 (443 hom., cov: 33)
  • Exomes 𝑓: 0.0045 (485 hom.)
• Consequence: AGRN NM_198576.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.812

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]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_198576.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.0013242364).
• BP6: Variant 1-1050446-G-A is Benign according to our data. Variant chr1-1050446-G-A is described in ClinVar as [Benign]. Clinvar id is 128312.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-1050446-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.148 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AGRN	NM_198576.4	c.4996G>A	p.Val1666Ile	missense_variant	29/36	ENST00000379370.7	NP_940978.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AGRN	ENST00000379370.7	c.4996G>A	p.Val1666Ile	missense_variant	29/36	1	NM_198576.4	ENSP00000368678.2
AGRN	ENST00000651234.1	c.4681G>A	p.Val1561Ile	missense_variant	28/38			ENSP00000499046.1
AGRN	ENST00000652369.1	c.4681G>A	p.Val1561Ile	missense_variant	28/35			ENSP00000498543.1
AGRN	ENST00000620552.4	c.4582G>A	p.Val1528Ile	missense_variant	29/39	5		ENSP00000484607.1

Frequencies

GnomAD3 genomes AF: 0.0435 AC: 6620 AN: 152092 Hom.: 443 Cov.: 33

Gnomad AFR AF: 0.152

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0156

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000471

Gnomad OTH AF: 0.0316

GnomAD3 exomes AF: 0.0112 AC: 2786 AN: 248120 Hom.: 189 AF XY: 0.00808 AC XY: 1090 AN XY: 134872

Gnomad AFR exome AF: 0.156

Gnomad AMR exome AF: 0.00688

Gnomad ASJ exome AF: 0.000201

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000323

Gnomad OTH exome AF: 0.00379

GnomAD4 exome AF: 0.00447 AC: 6532 AN: 1460716 Hom.: 485 Cov.: 34 AF XY: 0.00382 AC XY: 2776 AN XY: 726680

Gnomad4 AFR exome AF: 0.160

Gnomad4 AMR exome AF: 0.00785

Gnomad4 ASJ exome AF: 0.000192

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000170

Gnomad4 OTH exome AF: 0.00911

GnomAD4 genome AF: 0.0435 AC: 6626 AN: 152210 Hom.: 443 Cov.: 33 AF XY: 0.0420 AC XY: 3127 AN XY: 74424

Gnomad4 AFR AF: 0.151

Gnomad4 AMR AF: 0.0156

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000471

Gnomad4 OTH AF: 0.0313

Alfa AF: 0.0134 Hom.: 105

Bravo AF: 0.0496

ESP6500AA AF: 0.152 AC: 669

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.0134 AC: 1620

Asia WGS AF: 0.00866 AC: 30 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000593

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 15, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Congenital myasthenic syndrome 8 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	20
DANN	Benign	0.79
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.73	T;T
MetaRNN	Benign	0.0013	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.46	N;.
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.26	N;.
REVEL	Benign	0.19
Sift	Benign	0.30	T;.
Sift4G	Benign	0.13	T;T
Vest4		0.20
MPC		0.13
ClinPred		0.0047	T
GERP RS		1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.42

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs17160775; hg19: chr1-985826;