rs114389542

chr1-1044455-G-Achr1-1044455-G-Cchr1-1044455-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_198576.4(AGRN):c.2254+16G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00735 in 1,597,636 control chromosomes in the GnomAD database, including 212 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (85 hom., cov: 33)
  • Exomes 𝑓: 0.0058 (127 hom.)
• Consequence: AGRN NM_198576.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.288

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 (BayesDel_noAF=-0.9).
• BP6: Variant 1-1044455-G-A is Benign according to our data. Variant chr1-1044455-G-A is described in ClinVar as [Benign]. Clinvar id is 263168.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0608 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AGRN	NM_198576.4	c.2254+16G>A		intron_variant		ENST00000379370.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AGRN	ENST00000379370.7	c.2254+16G>A		intron_variant		1	NM_198576.4	P1
AGRN	ENST00000620552.4	c.1840+16G>A		intron_variant		5
AGRN	ENST00000651234.1	c.1939+16G>A		intron_variant
AGRN	ENST00000652369.1	c.1939+16G>A		intron_variant

Frequencies

GnomAD3 genomes AF: 0.0223 AC: 3391 AN: 152220 Hom.: 85 Cov.: 33

Gnomad AFR AF: 0.0627

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0114

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.0317

Gnomad SAS AF: 0.00993

Gnomad FIN AF: 0.0190

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00245

Gnomad OTH AF: 0.0115

GnomAD3 exomes AF: 0.0114 AC: 2459 AN: 216482 Hom.: 38 AF XY: 0.0106 AC XY: 1247 AN XY: 117884

Gnomad AFR exome AF: 0.0635

Gnomad AMR exome AF: 0.00645

Gnomad ASJ exome AF: 0.00612

Gnomad EAS exome AF: 0.0271

Gnomad SAS exome AF: 0.00843

Gnomad FIN exome AF: 0.0203

Gnomad NFE exome AF: 0.00295

Gnomad OTH exome AF: 0.00948

GnomAD4 exome AF: 0.00577 AC: 8335 AN: 1445298 Hom.: 127 Cov.: 34 AF XY: 0.00566 AC XY: 4065 AN XY: 717890

Gnomad4 AFR exome AF: 0.0651

Gnomad4 AMR exome AF: 0.00646

Gnomad4 ASJ exome AF: 0.00557

Gnomad4 EAS exome AF: 0.0295

Gnomad4 SAS exome AF: 0.00913

Gnomad4 FIN exome AF: 0.0183

Gnomad4 NFE exome AF: 0.00208

Gnomad4 OTH exome AF: 0.00951

GnomAD4 genome AF: 0.0223 AC: 3403 AN: 152338 Hom.: 85 Cov.: 33 AF XY: 0.0231 AC XY: 1720 AN XY: 74502

Gnomad4 AFR AF: 0.0628

Gnomad4 AMR AF: 0.0114

Gnomad4 ASJ AF: 0.00375

Gnomad4 EAS AF: 0.0316

Gnomad4 SAS AF: 0.0101

Gnomad4 FIN AF: 0.0190

Gnomad4 NFE AF: 0.00245

Gnomad4 OTH AF: 0.0114

Alfa AF: 0.00435 Hom.: 2

Bravo AF: 0.0227

Asia WGS AF: 0.0220 AC: 76 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 31, 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. -

Congenital myasthenic syndrome 8 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 24, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	1.7
Dann	Benign	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: rs114389542; hg19: chr1-979835; COSMIC: COSV65070999; COSMIC: COSV65070999;