NM_198576.4:c.1384+28G>A

Variant names:

• chr1-1042190-G-A
• rs2710876
• NM_198576.4:c.1384+28G>A

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.1384+28G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.897 in 1,576,312 control chromosomes in the GnomAD database, including 643,747 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.79 (50654 hom., cov: 34)
  • Exomes 𝑓: 0.91 (593093 hom.)
• Consequence: AGRN NM_198576.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.73
• 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: DEFINITIVE, STRONG Submitted by: ClinGen, 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=-0.84).
• BP6: Variant 1-1042190-G-A is Benign according to our data. Variant chr1-1042190-G-A is described in ClinVar as Benign. ClinVar VariationId is 263159.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.946 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198576.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGRN	NM_198576.4	MANE Select	c.1384+28G>A		intron	N/A	NP_940978.2
	AGRN	NM_001305275.2		c.1384+28G>A		intron	N/A	NP_001292204.1	O00468-1
	AGRN	NM_001364727.2		c.1069+28G>A		intron	N/A	NP_001351656.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGRN	ENST00000379370.7	TSL:1 MANE Select	c.1384+28G>A		intron	N/A	ENSP00000368678.2	O00468-6
	AGRN	ENST00000651234.1		c.1069+28G>A		intron	N/A	ENSP00000499046.1	A0A494C1I6
	AGRN	ENST00000652369.2		c.1069+28G>A		intron	N/A	ENSP00000498543.1	A0A494C0G5

Frequencies

GnomAD3 genomes AF: 0.788 AC: 119832 AN: 152074 Hom.: 50662 Cov.: 34

Gnomad AFR AF: 0.441

Gnomad AMI AF: 0.986

Gnomad AMR AF: 0.883

Gnomad ASJ AF: 0.920

Gnomad EAS AF: 0.968

Gnomad SAS AF: 0.947

Gnomad FIN AF: 0.940

Gnomad MID AF: 0.879

Gnomad NFE AF: 0.918

Gnomad OTH AF: 0.825

GnomAD2 exomes AF: 0.897 AC: 193293 AN: 215414 AF XY: 0.905

Gnomad AFR exome AF: 0.435

Gnomad AMR exome AF: 0.932

Gnomad ASJ exome AF: 0.918

Gnomad EAS exome AF: 0.973

Gnomad FIN exome AF: 0.937

Gnomad NFE exome AF: 0.915

Gnomad OTH exome AF: 0.899

GnomAD4 exome AF: 0.909 AC: 1294784 AN: 1424120 Hom.: 593093 Cov.: 45 AF XY: 0.911 AC XY: 642591 AN XY: 704992

African (AFR) AF: 0.418 AC: 13784 AN: 33006

American (AMR) AF: 0.925 AC: 40133 AN: 43406

Ashkenazi Jewish (ASJ) AF: 0.915 AC: 23040 AN: 25186

East Asian (EAS) AF: 0.970 AC: 37881 AN: 39062

South Asian (SAS) AF: 0.943 AC: 79304 AN: 84054

European-Finnish (FIN) AF: 0.932 AC: 35517 AN: 38090

Middle Eastern (MID) AF: 0.851 AC: 4782 AN: 5616

European-Non Finnish (NFE) AF: 0.919 AC: 1007802 AN: 1096634

Other (OTH) AF: 0.890 AC: 52541 AN: 59066

GnomAD4 genome AF: 0.787 AC: 119841 AN: 152192 Hom.: 50654 Cov.: 34 AF XY: 0.793 AC XY: 59006 AN XY: 74430

African (AFR) AF: 0.441 AC: 18266 AN: 41466

American (AMR) AF: 0.883 AC: 13521 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.920 AC: 3192 AN: 3470

East Asian (EAS) AF: 0.968 AC: 5011 AN: 5176

South Asian (SAS) AF: 0.946 AC: 4568 AN: 4830

European-Finnish (FIN) AF: 0.940 AC: 9981 AN: 10620

Middle Eastern (MID) AF: 0.873 AC: 255 AN: 292

European-Non Finnish (NFE) AF: 0.918 AC: 62401 AN: 68008

Other (OTH) AF: 0.826 AC: 1747 AN: 2114

Alfa AF: 0.863 Hom.: 10711

Bravo AF: 0.766

Asia WGS AF: 0.921 AC: 3205 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Congenital myasthenic syndrome 8 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.15
DANN	Benign	0.66
PhyloP100		-1.7
RBP_binding_hub_radar		0.85
RBP_regulation_power_radar		2.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2710876; hg19: chr1-977570;