1-1049886-C-T

Position:

• chr1-1049886-C-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.4745-17C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.54 in 1,611,140 control chromosomes in the GnomAD database, including 244,064 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.45 (18227 hom., cov: 31)
  • Exomes 𝑓: 0.55 (225837 hom.)
• Consequence: AGRN NM_198576.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.75

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=-0.86).
• BP6: Variant 1-1049886-C-T is Benign according to our data. Variant chr1-1049886-C-T is described in ClinVar as [Benign]. Clinvar id is 263188.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-1049886-C-T is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.788 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AGRN	NM_198576.4	c.4745-17C>T		intron_variant		ENST00000379370.7	NP_940978.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AGRN	ENST00000379370.7	c.4745-17C>T		intron_variant		1	NM_198576.4	ENSP00000368678.2
AGRN	ENST00000651234.1	c.4430-17C>T		intron_variant				ENSP00000499046.1
AGRN	ENST00000652369.1	c.4430-17C>T		intron_variant				ENSP00000498543.1
AGRN	ENST00000620552.4	c.4331-17C>T		intron_variant		5		ENSP00000484607.1

Frequencies

GnomAD3 genomes AF: 0.452 AC: 68428 AN: 151336 Hom.: 18221 Cov.: 31

Gnomad AFR AF: 0.161

Gnomad AMI AF: 0.595

Gnomad AMR AF: 0.624

Gnomad ASJ AF: 0.544

Gnomad EAS AF: 0.809

Gnomad SAS AF: 0.549

Gnomad FIN AF: 0.525

Gnomad MID AF: 0.506

Gnomad NFE AF: 0.537

Gnomad OTH AF: 0.480

GnomAD3 exomes AF: 0.557 AC: 133962 AN: 240300 Hom.: 39971 AF XY: 0.556 AC XY: 73327 AN XY: 131784

Gnomad AFR exome AF: 0.148

Gnomad AMR exome AF: 0.711

Gnomad ASJ exome AF: 0.544

Gnomad EAS exome AF: 0.810

Gnomad SAS exome AF: 0.545

Gnomad FIN exome AF: 0.529

Gnomad NFE exome AF: 0.535

Gnomad OTH exome AF: 0.542

GnomAD4 exome AF: 0.550 AC: 802180 AN: 1459684 Hom.: 225837 Cov.: 86 AF XY: 0.549 AC XY: 398741 AN XY: 726164

Gnomad4 AFR exome AF: 0.142

Gnomad4 AMR exome AF: 0.697

Gnomad4 ASJ exome AF: 0.543

Gnomad4 EAS exome AF: 0.825

Gnomad4 SAS exome AF: 0.545

Gnomad4 FIN exome AF: 0.529

Gnomad4 NFE exome AF: 0.549

Gnomad4 OTH exome AF: 0.531

GnomAD4 genome AF: 0.452 AC: 68450 AN: 151456 Hom.: 18227 Cov.: 31 AF XY: 0.458 AC XY: 33856 AN XY: 73966

Gnomad4 AFR AF: 0.160

Gnomad4 AMR AF: 0.625

Gnomad4 ASJ AF: 0.544

Gnomad4 EAS AF: 0.809

Gnomad4 SAS AF: 0.548

Gnomad4 FIN AF: 0.525

Gnomad4 NFE AF: 0.537

Gnomad4 OTH AF: 0.485

Alfa AF: 0.506 Hom.: 4369

Bravo AF: 0.448

Asia WGS AF: 0.646 AC: 2246 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 19, 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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Congenital myasthenic syndrome 8 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.76
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: rs2275813; hg19: chr1-985266;