1-1044017-G-A

Position:

• chr1-1044017-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_198576.4(AGRN):​c.1993G>A​(p.Glu665Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00242 in 1,609,284 control chromosomes in the GnomAD database, including 25 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. E665D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0028 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0024 (23 hom.)
• Consequence: AGRN NM_198576.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 7.62

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0114509165).
• BP6: Variant 1-1044017-G-A is Benign according to our data. Variant chr1-1044017-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 210106.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-1044017-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00277 (422/152368) while in subpopulation NFE AF= 0.00428 (291/68034). AF 95% confidence interval is 0.00387. There are 2 homozygotes in gnomad4. There are 214 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AGRN	NM_198576.4	c.1993G>A	p.Glu665Lys	missense_variant	10/36	ENST00000379370.7	NP_940978.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AGRN	ENST00000379370.7	c.1993G>A	p.Glu665Lys	missense_variant	10/36	1	NM_198576.4	ENSP00000368678.2
AGRN	ENST00000651234.1	c.1678G>A	p.Glu560Lys	missense_variant	9/38			ENSP00000499046.1
AGRN	ENST00000652369.1	c.1678G>A	p.Glu560Lys	missense_variant	9/35			ENSP00000498543.1
AGRN	ENST00000620552.4	c.1579G>A	p.Glu527Lys	missense_variant	10/39	5		ENSP00000484607.1

Frequencies

GnomAD3 genomes AF: 0.00277 AC: 422 AN: 152250 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000654

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00998

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00428

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00275 AC: 662 AN: 240846 Hom.: 4 AF XY: 0.00259 AC XY: 341 AN XY: 131722

Gnomad AFR exome AF: 0.000200

Gnomad AMR exome AF: 0.000614

Gnomad ASJ exome AF: 0.00172

Gnomad EAS exome AF: 0.000111

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0116

Gnomad NFE exome AF: 0.00349

Gnomad OTH exome AF: 0.00338

GnomAD4 exome AF: 0.00238 AC: 3473 AN: 1456916 Hom.: 23 Cov.: 35 AF XY: 0.00245 AC XY: 1776 AN XY: 724910

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.000606

Gnomad4 ASJ exome AF: 0.00138

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.0111

Gnomad4 NFE exome AF: 0.00245

Gnomad4 OTH exome AF: 0.00201

GnomAD4 genome AF: 0.00277 AC: 422 AN: 152368 Hom.: 2 Cov.: 33 AF XY: 0.00287 AC XY: 214 AN XY: 74510

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.000653

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00998

Gnomad4 NFE AF: 0.00428

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00380 Hom.: 1

Bravo AF: 0.00152

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00350 AC: 30

ExAC AF: 0.00309 AC: 373

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 31, 2018	See Variant Classification Assertion Criteria. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	AGRN: BS2 -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 13, 2017

- -

AGRN-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 18, 2019

This variant is classified as likely 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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 22, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	24
DANN	Uncertain	1.0
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D;D
MetaRNN	Benign	0.011	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.85	L;.
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-2.3	N;.
REVEL	Benign	0.28
Sift	Benign	0.33	T;.
Sift4G	Uncertain	0.033	D;D
Vest4		0.58
MVP		0.71
MPC		0.43
ClinPred		0.056	T
GERP RS		4.4
gMVP		0.44

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: rs143324306; hg19: chr1-979397;