rs2799066

Variant names:

• chr1-1041950-T-C
• rs2799066
• NM_198576.4:c.1178-6T>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.1178-6T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.918 in 1,602,914 control chromosomes in the GnomAD database, including 677,221 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.87 (58337 hom., cov: 32)
  • Exomes 𝑓: 0.92 (618884 hom.)
• Consequence: AGRN NM_198576.4 splice_region, intron
• Scores: Splicing: ADA: 0.000008463
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.844
• Publications: 12 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=-0.88).
• BP6: Variant 1-1041950-T-C is Benign according to our data. Variant chr1-1041950-T-C is described in ClinVar as Benign. ClinVar VariationId is 128292.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.977 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGRN	NM_198576.4	c.1178-6T>C		splice_region_variant, intron_variant	Intron 6 of 35	ENST00000379370.7	NP_940978.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGRN	ENST00000379370.7	c.1178-6T>C		splice_region_variant, intron_variant	Intron 6 of 35	1	NM_198576.4	ENSP00000368678.2
AGRN	ENST00000651234.1	c.863-6T>C		splice_region_variant, intron_variant	Intron 5 of 37			ENSP00000499046.1
AGRN	ENST00000652369.2	c.863-6T>C		splice_region_variant, intron_variant	Intron 5 of 34			ENSP00000498543.1
AGRN	ENST00000620552.4	c.764-6T>C		splice_region_variant, intron_variant	Intron 6 of 38	5		ENSP00000484607.1

Frequencies

GnomAD3 genomes AF: 0.873 AC: 131987 AN: 151164 Hom.: 58337 Cov.: 32

Gnomad AFR AF: 0.717

Gnomad AMI AF: 0.986

Gnomad AMR AF: 0.922

Gnomad ASJ AF: 0.927

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.957

Gnomad FIN AF: 0.959

Gnomad MID AF: 0.892

Gnomad NFE AF: 0.922

Gnomad OTH AF: 0.886

GnomAD2 exomes AF: 0.923 AC: 226454 AN: 245272 AF XY: 0.927

Gnomad AFR exome AF: 0.711

Gnomad AMR exome AF: 0.951

Gnomad ASJ exome AF: 0.925

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 0.954

Gnomad NFE exome AF: 0.918

Gnomad OTH exome AF: 0.919

GnomAD4 exome AF: 0.922 AC: 1339113 AN: 1451632 Hom.: 618884 Cov.: 62 AF XY: 0.924 AC XY: 667607 AN XY: 722596

African (AFR) AF: 0.696 AC: 21735 AN: 31236

American (AMR) AF: 0.947 AC: 42176 AN: 44538

Ashkenazi Jewish (ASJ) AF: 0.922 AC: 23974 AN: 26006

East Asian (EAS) AF: 1.00 AC: 39667 AN: 39672

South Asian (SAS) AF: 0.953 AC: 81601 AN: 85648

European-Finnish (FIN) AF: 0.951 AC: 49228 AN: 51748

Middle Eastern (MID) AF: 0.879 AC: 4714 AN: 5362

European-Non Finnish (NFE) AF: 0.922 AC: 1021135 AN: 1107432

Other (OTH) AF: 0.915 AC: 54883 AN: 59990

GnomAD4 genome AF: 0.873 AC: 132028 AN: 151282 Hom.: 58337 Cov.: 32 AF XY: 0.876 AC XY: 64804 AN XY: 73948

African (AFR) AF: 0.716 AC: 29167 AN: 40730

American (AMR) AF: 0.922 AC: 14101 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.927 AC: 3217 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5123 AN: 5124

South Asian (SAS) AF: 0.957 AC: 4613 AN: 4822

European-Finnish (FIN) AF: 0.959 AC: 10168 AN: 10604

Middle Eastern (MID) AF: 0.891 AC: 262 AN: 294

European-Non Finnish (NFE) AF: 0.922 AC: 62606 AN: 67916

Other (OTH) AF: 0.887 AC: 1872 AN: 2110

Alfa AF: 0.910 Hom.: 20421

Bravo AF: 0.862

Asia WGS AF: 0.956 AC: 3306 AN: 3458

EpiCase AF: 0.916

EpiControl AF: 0.909

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 19, 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. -

Aug 15, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Congenital myasthenic syndrome 8 Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.90
DANN	Benign	0.35
PhyloP100		-0.84
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0000085
dbscSNV1_RF	Benign	0.0020
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

Other links and lift over

dbSNP: rs2799066; hg19: chr1-977330;