rs139886237

Positions:

• chr1-1044176-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_198576.4(AGRN):​c.2067G>A​(p.Gln689=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00362 in 1,613,266 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0028 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0037 (22 hom.)
• Consequence: AGRN NM_198576.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.33

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 1-1044176-G-A is Benign according to our data. Variant chr1-1044176-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 263167.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.33 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00284 (432/152322) while in subpopulation NFE AF= 0.0045 (306/68018). AF 95% confidence interval is 0.00408. There are 0 homozygotes in gnomad4. There are 181 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 22 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AGRN	NM_198576.4	c.2067G>A	p.Gln689=	synonymous_variant	11/36	ENST00000379370.7	NP_940978.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AGRN	ENST00000379370.7	c.2067G>A	p.Gln689=	synonymous_variant	11/36	1	NM_198576.4	ENSP00000368678	P1
AGRN	ENST00000651234.1	c.1752G>A	p.Gln584=	synonymous_variant	10/38			ENSP00000499046
AGRN	ENST00000652369.1	c.1752G>A	p.Gln584=	synonymous_variant	10/35			ENSP00000498543
AGRN	ENST00000620552.4	c.1653G>A	p.Gln551=	synonymous_variant	11/39	5		ENSP00000484607

Frequencies

GnomAD3 genomes AF: 0.00284 AC: 432 AN: 152204 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000796

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00301

Gnomad ASJ AF: 0.00778

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000659

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00450

Gnomad OTH AF: 0.00526

GnomAD3 exomes AF: 0.00290 AC: 725 AN: 250430 Hom.: 3 AF XY: 0.00294 AC XY: 399 AN XY: 135712

Gnomad AFR exome AF: 0.000618

Gnomad AMR exome AF: 0.00301

Gnomad ASJ exome AF: 0.00827

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000327

Gnomad FIN exome AF: 0.00116

Gnomad NFE exome AF: 0.00421

Gnomad OTH exome AF: 0.00295

GnomAD4 exome AF: 0.00370 AC: 5402 AN: 1460944 Hom.: 22 Cov.: 35 AF XY: 0.00354 AC XY: 2574 AN XY: 726824

Gnomad4 AFR exome AF: 0.000478

Gnomad4 AMR exome AF: 0.00279

Gnomad4 ASJ exome AF: 0.00773

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000394

Gnomad4 FIN exome AF: 0.00135

Gnomad4 NFE exome AF: 0.00424

Gnomad4 OTH exome AF: 0.00354

GnomAD4 genome AF: 0.00284 AC: 432 AN: 152322 Hom.: 0 Cov.: 33 AF XY: 0.00243 AC XY: 181 AN XY: 74496

Gnomad4 AFR AF: 0.000794

Gnomad4 AMR AF: 0.00300

Gnomad4 ASJ AF: 0.00778

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000659

Gnomad4 NFE AF: 0.00450

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00400 Hom.: 1

Bravo AF: 0.00303

EpiCase AF: 0.00447

EpiControl AF: 0.00581

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	AGRN: BP4, BP7 -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 20, 2019	- -

AGRN-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 08, 2019

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	4.8
DANN	Benign	0.61
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.8

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: rs139886237; hg19: chr1-979556;