rs191270495

Positions:

• chr1-1041174-C-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_198576.4(AGRN):​c.729C>G​(p.Gly243=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00224 in 1,399,664 control chromosomes in the GnomAD database, including 61 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0092 (30 hom., cov: 31)
  • Exomes 𝑓: 0.0014 (31 hom.)
• Consequence: AGRN NM_198576.4 splice_region, synonymous
• Scores: Splicing: ADA: 0.00002772
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.244

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 1-1041174-C-G is Benign according to our data. Variant chr1-1041174-C-G is described in ClinVar as [Benign]. Clinvar id is 263202.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.244 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00916 (1357/148196) while in subpopulation AFR AF= 0.0248 (970/39084). AF 95% confidence interval is 0.0235. There are 30 homozygotes in gnomad4. There are 680 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 30 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AGRN	NM_198576.4	c.729C>G	p.Gly243=	splice_region_variant, synonymous_variant	5/36	ENST00000379370.7	NP_940978.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AGRN	ENST00000379370.7	c.729C>G	p.Gly243=	splice_region_variant, synonymous_variant	5/36	1	NM_198576.4	ENSP00000368678	P1

Frequencies

GnomAD3 genomes AF: 0.00912 AC: 1350 AN: 148100 Hom.: 30 Cov.: 31

Gnomad AFR AF: 0.0247

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00696

Gnomad ASJ AF: 0.00290

Gnomad EAS AF: 0.0145

Gnomad SAS AF: 0.00419

Gnomad FIN AF: 0.00918

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00114

Gnomad OTH AF: 0.00485

GnomAD3 exomes AF: 0.00564 AC: 289 AN: 51286 Hom.: 1 AF XY: 0.00581 AC XY: 178 AN XY: 30632

Gnomad AFR exome AF: 0.0326

Gnomad AMR exome AF: 0.00340

Gnomad ASJ exome AF: 0.00574

Gnomad EAS exome AF: 0.0195

Gnomad SAS exome AF: 0.00701

Gnomad FIN exome AF: 0.0146

Gnomad NFE exome AF: 0.00211

Gnomad OTH exome AF: 0.00940

GnomAD4 exome AF: 0.00142 AC: 1780 AN: 1251468 Hom.: 31 Cov.: 33 AF XY: 0.00139 AC XY: 855 AN XY: 615400

Gnomad4 AFR exome AF: 0.0135

Gnomad4 AMR exome AF: 0.00204

Gnomad4 ASJ exome AF: 0.00163

Gnomad4 EAS exome AF: 0.0197

Gnomad4 SAS exome AF: 0.000701

Gnomad4 FIN exome AF: 0.0109

Gnomad4 NFE exome AF: 0.000330

Gnomad4 OTH exome AF: 0.00327

GnomAD4 genome AF: 0.00916 AC: 1357 AN: 148196 Hom.: 30 Cov.: 31 AF XY: 0.00940 AC XY: 680 AN XY: 72358

Gnomad4 AFR AF: 0.0248

Gnomad4 AMR AF: 0.00695

Gnomad4 ASJ AF: 0.00290

Gnomad4 EAS AF: 0.0144

Gnomad4 SAS AF: 0.00419

Gnomad4 FIN AF: 0.00918

Gnomad4 NFE AF: 0.00114

Gnomad4 OTH AF: 0.00480

Alfa AF: 0.0106 Hom.: 3

Bravo AF: 0.0189

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	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. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 27, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Congenital myasthenic syndrome 8 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 24, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	4.9
DANN	Benign	0.72
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.8

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000028
SpliceAI score (max)		0.010		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: rs191270495; hg19: chr1-976554; COSMIC: COSV65070398; COSMIC: COSV65070398;