rs147681220

Positions:

• chr1-1050807-C-T

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.5223C>T​(p.Gly1741Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00556 in 1,592,094 control chromosomes in the GnomAD database, including 112 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0077 (25 hom., cov: 33)
  • Exomes 𝑓: 0.0053 (87 hom.)
• Consequence: AGRN NM_198576.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.25

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=-0.67).
• BP6: Variant 1-1050807-C-T is Benign according to our data. Variant chr1-1050807-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 474144.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.25 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00774 (1178/152182) while in subpopulation NFE AF= 0.00546 (371/67974). AF 95% confidence interval is 0.005. There are 25 homozygotes in gnomad4. There are 761 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 25 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AGRN	NM_198576.4	c.5223C>T	p.Gly1741Gly	synonymous_variant	30/36	ENST00000379370.7	NP_940978.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AGRN	ENST00000379370.7	c.5223C>T	p.Gly1741Gly	synonymous_variant	30/36	1	NM_198576.4	ENSP00000368678.2
AGRN	ENST00000651234.1	c.4908C>T	p.Gly1636Gly	synonymous_variant	29/38			ENSP00000499046.1
AGRN	ENST00000652369.1	c.4908C>T	p.Gly1636Gly	synonymous_variant	29/35			ENSP00000498543.1
AGRN	ENST00000620552.4	c.4809C>T	p.Gly1603Gly	synonymous_variant	30/39	5		ENSP00000484607.1

Frequencies

GnomAD3 genomes AF: 0.00775 AC: 1178 AN: 152064 Hom.: 25 Cov.: 33

Gnomad AFR AF: 0.000676

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00309

Gnomad SAS AF: 0.00477

Gnomad FIN AF: 0.0647

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00546

Gnomad OTH AF: 0.00383

GnomAD3 exomes AF: 0.00793 AC: 1680 AN: 211816 Hom.: 21 AF XY: 0.00775 AC XY: 897 AN XY: 115688

Gnomad AFR exome AF: 0.000534

Gnomad AMR exome AF: 0.00486

Gnomad ASJ exome AF: 0.000323

Gnomad EAS exome AF: 0.000489

Gnomad SAS exome AF: 0.00496

Gnomad FIN exome AF: 0.0552

Gnomad NFE exome AF: 0.00592

Gnomad OTH exome AF: 0.0100

GnomAD4 exome AF: 0.00533 AC: 7681 AN: 1439912 Hom.: 87 Cov.: 34 AF XY: 0.00535 AC XY: 3827 AN XY: 715272

Gnomad4 AFR exome AF: 0.000511

Gnomad4 AMR exome AF: 0.00501

Gnomad4 ASJ exome AF: 0.000816

Gnomad4 EAS exome AF: 0.000308

Gnomad4 SAS exome AF: 0.00481

Gnomad4 FIN exome AF: 0.0522

Gnomad4 NFE exome AF: 0.00389

Gnomad4 OTH exome AF: 0.00515

GnomAD4 genome AF: 0.00774 AC: 1178 AN: 152182 Hom.: 25 Cov.: 33 AF XY: 0.0102 AC XY: 761 AN XY: 74376

Gnomad4 AFR AF: 0.000674

Gnomad4 AMR AF: 0.00262

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00310

Gnomad4 SAS AF: 0.00477

Gnomad4 FIN AF: 0.0647

Gnomad4 NFE AF: 0.00546

Gnomad4 OTH AF: 0.00379

Alfa AF: 0.00602 Hom.: 3

Bravo AF: 0.00272

Asia WGS AF: 0.00635 AC: 22 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 02, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2023	AGRN: BP4, BP7, BS2 -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

AGRN-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 02, 2024

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	-0.67
CADD	Benign	0.27
DANN	Benign	0.74
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs147681220; hg19: chr1-986187; COSMIC: COSV101038847; COSMIC: COSV101038847;