rs76264143

Variant names:

• chr1-1047464-G-C
• rs76264143
• NM_198576.4:c.3516+10G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_198576.4(AGRN):​c.3516+10G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0663 in 1,612,648 control chromosomes in the GnomAD database, including 3,950 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.051 (281 hom., cov: 34)
  • Exomes 𝑓: 0.068 (3669 hom.)
• Consequence: AGRN NM_198576.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.388
• Publications: 5 publications found

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]

AGRN Gene-Disease associations (from GenCC):

• congenital myasthenic syndrome 8

  Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• presynaptic congenital myasthenic syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• postsynaptic congenital myasthenic syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 1-1047464-G-C is Benign according to our data. Variant chr1-1047464-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 128301.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0733 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGRN	NM_198576.4	c.3516+10G>C		intron_variant	Intron 20 of 35	ENST00000379370.7	NP_940978.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGRN	ENST00000379370.7	c.3516+10G>C		intron_variant	Intron 20 of 35	1	NM_198576.4	ENSP00000368678.2

Frequencies

GnomAD3 genomes AF: 0.0514 AC: 7827 AN: 152206 Hom.: 281 Cov.: 34

Gnomad AFR AF: 0.0129

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.0497

Gnomad ASJ AF: 0.0956

Gnomad EAS AF: 0.000962

Gnomad SAS AF: 0.0782

Gnomad FIN AF: 0.0521

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.0751

Gnomad OTH AF: 0.0559

GnomAD2 exomes AF: 0.0581 AC: 14445 AN: 248474 AF XY: 0.0618

Gnomad AFR exome AF: 0.0111

Gnomad AMR exome AF: 0.0337

Gnomad ASJ exome AF: 0.0946

Gnomad EAS exome AF: 0.000273

Gnomad FIN exome AF: 0.0532

Gnomad NFE exome AF: 0.0736

Gnomad OTH exome AF: 0.0650

GnomAD4 exome AF: 0.0679 AC: 99140 AN: 1460324 Hom.: 3669 Cov.: 33 AF XY: 0.0690 AC XY: 50105 AN XY: 726456

African (AFR) AF: 0.0102 AC: 340 AN: 33454

American (AMR) AF: 0.0348 AC: 1552 AN: 44650

Ashkenazi Jewish (ASJ) AF: 0.0956 AC: 2497 AN: 26126

East Asian (EAS) AF: 0.000227 AC: 9 AN: 39700

South Asian (SAS) AF: 0.0796 AC: 6862 AN: 86234

European-Finnish (FIN) AF: 0.0526 AC: 2739 AN: 52106

Middle Eastern (MID) AF: 0.0924 AC: 533 AN: 5768

European-Non Finnish (NFE) AF: 0.0727 AC: 80865 AN: 1111914

Other (OTH) AF: 0.0620 AC: 3743 AN: 60372

GnomAD4 genome AF: 0.0513 AC: 7819 AN: 152324 Hom.: 281 Cov.: 34 AF XY: 0.0505 AC XY: 3761 AN XY: 74470

African (AFR) AF: 0.0129 AC: 536 AN: 41582

American (AMR) AF: 0.0496 AC: 759 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0956 AC: 332 AN: 3472

East Asian (EAS) AF: 0.000964 AC: 5 AN: 5186

South Asian (SAS) AF: 0.0783 AC: 378 AN: 4828

European-Finnish (FIN) AF: 0.0521 AC: 554 AN: 10628

Middle Eastern (MID) AF: 0.0850 AC: 25 AN: 294

European-Non Finnish (NFE) AF: 0.0750 AC: 5102 AN: 68004

Other (OTH) AF: 0.0549 AC: 116 AN: 2114

Alfa AF: 0.0677 Hom.: 91

Bravo AF: 0.0482

Asia WGS AF: 0.0280 AC: 101 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Feb 04, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Sep 28, 2016

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Congenital myasthenic syndrome 8 Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.0
DANN	Benign	0.40
PhyloP100		0.39
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs76264143; hg19: chr1-982844;