chr1-1051248-C-T

Position:

• chr1-1051248-C-T

Variant summary

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

The ENST00000379370.7(AGRN):​c.5254-5C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00369 in 1,580,848 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0024 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0038 (14 hom.)
• Consequence: AGRN ENST00000379370.7 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00001593
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.0540

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=-0.77).
• BP6: Variant 1-1051248-C-T is Benign according to our data. Variant chr1-1051248-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 474146.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-1051248-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0024 (366/152280) while in subpopulation NFE AF= 0.00462 (314/68000). AF 95% confidence interval is 0.0042. There are 2 homozygotes in gnomad4. There are 150 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.5254-5C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000379370.7	NP_940978.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AGRN	ENST00000379370.7	c.5254-5C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_198576.4	ENSP00000368678	P1
AGRN	ENST00000620552.4	c.4852-5C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5		ENSP00000484607
AGRN	ENST00000651234.1	c.4951-5C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant				ENSP00000499046
AGRN	ENST00000652369.1	c.4939-5C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant				ENSP00000498543

Frequencies

GnomAD3 genomes AF: 0.00241 AC: 366 AN: 152162 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000797

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000847

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00462

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00226 AC: 441 AN: 194880 Hom.: 1 AF XY: 0.00214 AC XY: 225 AN XY: 105176

Gnomad AFR exome AF: 0.000518

Gnomad AMR exome AF: 0.000546

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000397

Gnomad FIN exome AF: 0.00170

Gnomad NFE exome AF: 0.00444

Gnomad OTH exome AF: 0.00180

GnomAD4 exome AF: 0.00383 AC: 5469 AN: 1428568 Hom.: 14 Cov.: 37 AF XY: 0.00361 AC XY: 2553 AN XY: 707624

Gnomad4 AFR exome AF: 0.000761

Gnomad4 AMR exome AF: 0.000572

Gnomad4 ASJ exome AF: 0.0000392

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000368

Gnomad4 FIN exome AF: 0.00169

Gnomad4 NFE exome AF: 0.00462

Gnomad4 OTH exome AF: 0.00402

GnomAD4 genome AF: 0.00240 AC: 366 AN: 152280 Hom.: 2 Cov.: 33 AF XY: 0.00201 AC XY: 150 AN XY: 74456

Gnomad4 AFR AF: 0.000794

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000847

Gnomad4 NFE AF: 0.00462

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00296 Hom.: 1

Bravo AF: 0.00247

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2022	AGRN: BP4 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 28, 2020	- -

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	-0.77
CADD	Benign	2.9
DANN	Benign	0.75
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000016
dbscSNV1_RF	Benign	0.0
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: rs34708466; hg19: chr1-986628;