chr1-1020239-G-C

Variant names:

• chr1-1020239-G-C
• rs201073369
• NM_198576.4:c.67G>C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_198576.4(AGRN):​c.67G>C​(p.Val23Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00708 in 1,445,836 control chromosomes in the GnomAD database, including 111 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V23G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0067 (15 hom., cov: 33)
  • Exomes 𝑓: 0.0071 (96 hom.)
• Consequence: AGRN NM_198576.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 0.455

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0018510222).
• BP6: Variant 1-1020239-G-C is Benign according to our data. Variant chr1-1020239-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 210112.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=1, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00673 (1021/151818) while in subpopulation SAS AF= 0.0311 (150/4830). AF 95% confidence interval is 0.027. There are 15 homozygotes in gnomad4. There are 512 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 15 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGRN	NM_198576.4	c.67G>C	p.Val23Leu	missense_variant	Exon 1 of 36	ENST00000379370.7	NP_940978.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGRN	ENST00000379370.7	c.67G>C	p.Val23Leu	missense_variant	Exon 1 of 36	1	NM_198576.4	ENSP00000368678.2
AGRN	ENST00000620552	c.-348G>C		5_prime_UTR_variant	Exon 1 of 39	5		ENSP00000484607.1

Frequencies

GnomAD3 genomes AF: 0.00674 AC: 1022 AN: 151712 Hom.: 15 Cov.: 33

Gnomad AFR AF: 0.00430

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00315

Gnomad ASJ AF: 0.0185

Gnomad EAS AF: 0.00502

Gnomad SAS AF: 0.0308

Gnomad FIN AF: 0.00364

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.00735

Gnomad OTH AF: 0.00913

GnomAD3 exomes AF: 0.0119 AC: 905 AN: 75972 Hom.: 22 AF XY: 0.0147 AC XY: 642 AN XY: 43528

Gnomad AFR exome AF: 0.00535

Gnomad AMR exome AF: 0.00151

Gnomad ASJ exome AF: 0.0164

Gnomad EAS exome AF: 0.00305

Gnomad SAS exome AF: 0.0337

Gnomad FIN exome AF: 0.00371

Gnomad NFE exome AF: 0.00672

Gnomad OTH exome AF: 0.00779

GnomAD4 exome AF: 0.00712 AC: 9212 AN: 1294018 Hom.: 96 Cov.: 32 AF XY: 0.00801 AC XY: 5109 AN XY: 637466

Gnomad4 AFR exome AF: 0.00445

Gnomad4 AMR exome AF: 0.00188

Gnomad4 ASJ exome AF: 0.0188

Gnomad4 EAS exome AF: 0.000990

Gnomad4 SAS exome AF: 0.0319

Gnomad4 FIN exome AF: 0.00543

Gnomad4 NFE exome AF: 0.00549

Gnomad4 OTH exome AF: 0.00884

GnomAD4 genome AF: 0.00673 AC: 1021 AN: 151818 Hom.: 15 Cov.: 33 AF XY: 0.00690 AC XY: 512 AN XY: 74248

Gnomad4 AFR AF: 0.00429

Gnomad4 AMR AF: 0.00315

Gnomad4 ASJ AF: 0.0185

Gnomad4 EAS AF: 0.00484

Gnomad4 SAS AF: 0.0311

Gnomad4 FIN AF: 0.00364

Gnomad4 NFE AF: 0.00735

Gnomad4 OTH AF: 0.00856

Alfa AF: 0.00180 Hom.: 0

Bravo AF: 0.00583

ExAC AF: 0.0136 AC: 314

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Jun 18, 2024

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

See Variant Classification Assertion Criteria. -

Oct 20, 2017

Athena Diagnostics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Uncertain:1

Sep 29, 2014

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

AGRN-related disorder Benign:1

Apr 05, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Congenital myasthenic syndrome 8 Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	12
DANN	Benign	0.43
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0066	N
LIST_S2	Benign	0.50	T
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.14	N
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-0.25	N
REVEL	Benign	0.040
Sift	Benign	0.63	T
Sift4G	Benign	0.19	T
Vest4		0.053
MPC		0.42
ClinPred		0.0045	T
GERP RS		1.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.19

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

Publications

LitVar

Other links and lift over

dbSNP: rs201073369; hg19: chr1-955619;