rs35881187

chr1-1043223-CCT-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_198576.4(AGRN):c.1385-15_1385-14del variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.543 in 1,587,886 control chromosomes in the GnomAD database, including 243,783 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.44 (18390 hom., cov: 0)
  • Exomes 𝑓: 0.55 (225393 hom.)
• Consequence: AGRN NM_198576.4 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.112

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 -16 ACMG points.

• BP6: Variant 1-1043223-CCT-C is Benign according to our data. Variant chr1-1043223-CCT-C is described in ClinVar as [Benign]. Clinvar id is 263160.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.765 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AGRN	NM_198576.4	c.1385-15_1385-14del		splice_polypyrimidine_tract_variant, intron_variant		ENST00000379370.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AGRN	ENST00000379370.7	c.1385-15_1385-14del		splice_polypyrimidine_tract_variant, intron_variant		1	NM_198576.4	P1
AGRN	ENST00000620552.4	c.971-15_971-14del		splice_polypyrimidine_tract_variant, intron_variant		5
AGRN	ENST00000651234.1	c.1070-15_1070-14del		splice_polypyrimidine_tract_variant, intron_variant
AGRN	ENST00000652369.1	c.1070-15_1070-14del		splice_polypyrimidine_tract_variant, intron_variant

Frequencies

GnomAD3 genomes AF: 0.443 AC: 67234 AN: 151712 Hom.: 18381 Cov.: 0

Gnomad AFR AF: 0.110

Gnomad AMI AF: 0.595

Gnomad AMR AF: 0.622

Gnomad ASJ AF: 0.557

Gnomad EAS AF: 0.786

Gnomad SAS AF: 0.555

Gnomad FIN AF: 0.537

Gnomad MID AF: 0.500

Gnomad NFE AF: 0.549

Gnomad OTH AF: 0.477

GnomAD3 exomes AF: 0.551 AC: 113916 AN: 206582 Hom.: 33576 AF XY: 0.552 AC XY: 61257 AN XY: 110960

Gnomad AFR exome AF: 0.0943

Gnomad AMR exome AF: 0.697

Gnomad ASJ exome AF: 0.546

Gnomad EAS exome AF: 0.786

Gnomad SAS exome AF: 0.546

Gnomad FIN exome AF: 0.535

Gnomad NFE exome AF: 0.539

Gnomad OTH exome AF: 0.539

GnomAD4 exome AF: 0.553 AC: 794283 AN: 1436056 Hom.: 225393 AF XY: 0.553 AC XY: 393599 AN XY: 711874

Gnomad4 AFR exome AF: 0.0899

Gnomad4 AMR exome AF: 0.684

Gnomad4 ASJ exome AF: 0.549

Gnomad4 EAS exome AF: 0.802

Gnomad4 SAS exome AF: 0.549

Gnomad4 FIN exome AF: 0.539

Gnomad4 NFE exome AF: 0.556

Gnomad4 OTH exome AF: 0.533

GnomAD4 genome AF: 0.443 AC: 67250 AN: 151830 Hom.: 18390 Cov.: 0 AF XY: 0.449 AC XY: 33341 AN XY: 74198

Gnomad4 AFR AF: 0.110

Gnomad4 AMR AF: 0.623

Gnomad4 ASJ AF: 0.557

Gnomad4 EAS AF: 0.786

Gnomad4 SAS AF: 0.554

Gnomad4 FIN AF: 0.537

Gnomad4 NFE AF: 0.549

Gnomad4 OTH AF: 0.482

Alfa AF: 0.504 Hom.: 3738

Bravo AF: 0.436

Asia WGS AF: 0.647 AC: 2252 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital myasthenic syndrome 8 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 27, 2016

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 29, 2018

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs35881187; hg19: chr1-978603;