rs113020870

Positions:

• chr1-1049997-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_198576.4(AGRN):​c.4839C>T​(p.Cys1613Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00422 in 1,513,062 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0030 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0044 (21 hom.)
• Consequence: AGRN NM_198576.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.325

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 1-1049997-C-T is Benign according to our data. Variant chr1-1049997-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 263189.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00296 (429/144898) while in subpopulation NFE AF= 0.00435 (288/66144). AF 95% confidence interval is 0.00394. There are 0 homozygotes in gnomad4. There are 212 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 21 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AGRN	NM_198576.4	c.4839C>T	p.Cys1613Cys	synonymous_variant	27/36	ENST00000379370.7	NP_940978.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AGRN	ENST00000379370.7	c.4839C>T	p.Cys1613Cys	synonymous_variant	27/36	1	NM_198576.4	ENSP00000368678.2
AGRN	ENST00000651234.1	c.4524C>T	p.Cys1508Cys	synonymous_variant	26/38			ENSP00000499046.1
AGRN	ENST00000652369.1	c.4524C>T	p.Cys1508Cys	synonymous_variant	26/35			ENSP00000498543.1
AGRN	ENST00000620552.4	c.4425C>T	p.Cys1475Cys	synonymous_variant	27/39	5		ENSP00000484607.1

Frequencies

GnomAD3 genomes AF: 0.00296 AC: 429 AN: 144784 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000995

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00373

Gnomad ASJ AF: 0.000592

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000479

Gnomad FIN AF: 0.00391

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00435

Gnomad OTH AF: 0.00294

GnomAD3 exomes AF: 0.00273 AC: 647 AN: 237116 Hom.: 2 AF XY: 0.00268 AC XY: 350 AN XY: 130706

Gnomad AFR exome AF: 0.000974

Gnomad AMR exome AF: 0.00129

Gnomad ASJ exome AF: 0.000415

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000430

Gnomad FIN exome AF: 0.00541

Gnomad NFE exome AF: 0.00427

Gnomad OTH exome AF: 0.00223

GnomAD4 exome AF: 0.00436 AC: 5961 AN: 1368164 Hom.: 21 Cov.: 72 AF XY: 0.00420 AC XY: 2856 AN XY: 680044

Gnomad4 AFR exome AF: 0.000700

Gnomad4 AMR exome AF: 0.00155

Gnomad4 ASJ exome AF: 0.000442

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000539

Gnomad4 FIN exome AF: 0.00485

Gnomad4 NFE exome AF: 0.00517

Gnomad4 OTH exome AF: 0.00288

GnomAD4 genome AF: 0.00296 AC: 429 AN: 144898 Hom.: 0 Cov.: 33 AF XY: 0.00300 AC XY: 212 AN XY: 70584

Gnomad4 AFR AF: 0.000993

Gnomad4 AMR AF: 0.00372

Gnomad4 ASJ AF: 0.000592

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000478

Gnomad4 FIN AF: 0.00391

Gnomad4 NFE AF: 0.00435

Gnomad4 OTH AF: 0.00291

Alfa AF: 0.00349 Hom.: 1

Bravo AF: 0.00258

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00463

EpiControl AF: 0.00339

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	Oct 09, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 27, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	AGRN: PP3, BS2 -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Congenital myasthenic syndrome 8 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 22, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	19
DANN	Benign	0.44
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.5

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.98		Position offset: -2
DS_DL_spliceai		0.60		Position offset: 40

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs113020870; hg19: chr1-985377; COSMIC: COSV65067910; COSMIC: COSV65067910;