rs376535149

Variant names:

• chr1-1050583-G-A
• rs376535149
• NM_198576.4:c.5133G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BP7

The NM_198576.4(AGRN):​c.5133G>A​(p.Ala1711Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000895 in 1,609,292 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000097 (0 hom.)
• Consequence: AGRN NM_198576.4 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.81
• Publications: 1 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.009).
• BP6: Variant 1-1050583-G-A is Benign according to our data. Variant chr1-1050583-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 541186.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.82 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGRN	NM_198576.4	c.5133G>A	p.Ala1711Ala	synonymous_variant	Exon 29 of 36	ENST00000379370.7	NP_940978.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGRN	ENST00000379370.7	c.5133G>A	p.Ala1711Ala	synonymous_variant	Exon 29 of 36	1	NM_198576.4	ENSP00000368678.2
AGRN	ENST00000651234.1	c.4818G>A	p.Ala1606Ala	synonymous_variant	Exon 28 of 38			ENSP00000499046.1
AGRN	ENST00000652369.2	c.4818G>A	p.Ala1606Ala	synonymous_variant	Exon 28 of 35			ENSP00000498543.1
AGRN	ENST00000620552.4	c.4719G>A	p.Ala1573Ala	synonymous_variant	Exon 29 of 39	5		ENSP00000484607.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152092 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000491 AC: 12 AN: 244414 AF XY: 0.0000450

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000168

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000818

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000974 AC: 142 AN: 1457200 Hom.: 0 Cov.: 35 AF XY: 0.0000870 AC XY: 63 AN XY: 724488

African (AFR) AF: 0.000180 AC: 6 AN: 33390

American (AMR) AF: 0.00 AC: 0 AN: 44606

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26036

East Asian (EAS) AF: 0.000253 AC: 10 AN: 39600

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86156

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51514

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5728

European-Non Finnish (NFE) AF: 0.000110 AC: 122 AN: 1109962

Other (OTH) AF: 0.0000498 AC: 3 AN: 60208

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152092 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74284

African (AFR) AF: 0.0000242 AC: 1 AN: 41400

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67992

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000447 Hom.: 0

Bravo AF: 0.00000756

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Jul 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

AGRN: BP4, BP7 -

Congenital myasthenic syndrome 8 Benign:1

May 30, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely 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	-0.75
CADD	Benign	0.083
DANN	Benign	0.83
PhyloP100		-2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs376535149; hg19: chr1-985963; COSMIC: COSV65070281; COSMIC: COSV65070281;