rs1553177542

Variant names:

• chr1-1049050-TGCAGCTCAGGTGGGCGGGGAGGGGACGGGGCCGGGGCAGCTCAGGTGGGCGGGGAGGGGACGGGCGGGGGAGGGGGGGCCGGG-T
• rs1553177542
• NM_198576.4:c.4298+6_4298+88delCGGGGAGGGGACGGGGCCGGGGCAGCTCAGGTGGGCGGGGAGGGGACGGGCGGGGGAGGGGGGGCCGGGGCAGCTCAGGTGGG

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 8P and 16B. PVS1 BP6_Very_Strong BS1 BS2

The ENST00000379370.7(AGRN):​c.4290_4298+74delGCAGCTCAGGTGGGCGGGGAGGGGACGGGGCCGGGGCAGCTCAGGTGGGCGGGGAGGGGACGGGCGGGGGAGGGGGGGCCGGG​(p.Gln1431_Arg1433del) variant causes a splice donor, conservative inframe deletion, splice region, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00742 in 141,150 control chromosomes in the GnomAD database, including 8 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0074 (8 hom., cov: 24)
  • Exomes 𝑓: 0.00075 (13 hom.)
  • Failed GnomAD Quality Control
• Consequence: AGRN ENST00000379370.7 splice_donor, conservative_inframe_deletion, splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 9.20
• Publications: 0 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 -8 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• BP6: Variant 1-1049050-TGCAGCTCAGGTGGGCGGGGAGGGGACGGGGCCGGGGCAGCTCAGGTGGGCGGGGAGGGGACGGGCGGGGGAGGGGGGGCCGGG-T is Benign according to our data. Variant chr1-1049050-TGCAGCTCAGGTGGGCGGGGAGGGGACGGGGCCGGGGCAGCTCAGGTGGGCGGGGAGGGGACGGGCGGGGGAGGGGGGGCCGGG-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 541195.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00742 (1047/141150) while in subpopulation AFR AF = 0.0284 (993/34928). AF 95% confidence interval is 0.027. There are 8 homozygotes in GnomAd4. There are 514 alleles in the male GnomAd4 subpopulation. Median coverage is 24. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000379370.7. 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.4298+6_4298+88delCGGGGAGGGGACGGGGCCGGGGCAGCTCAGGTGGGCGGGGAGGGGACGGGCGGGGGAGGGGGGGCCGGGGCAGCTCAGGTGGG		splice_region intron	N/A	NP_940978.2
	AGRN	NM_001305275.2		c.4298+6_4298+88delCGGGGAGGGGACGGGGCCGGGGCAGCTCAGGTGGGCGGGGAGGGGACGGGCGGGGGAGGGGGGGCCGGGGCAGCTCAGGTGGG		splice_region intron	N/A	NP_001292204.1	O00468-1
	AGRN	NM_001364727.2		c.3983+6_3983+88delCGGGGAGGGGACGGGGCCGGGGCAGCTCAGGTGGGCGGGGAGGGGACGGGCGGGGGAGGGGGGGCCGGGGCAGCTCAGGTGGG		splice_region 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.4290_4298+74delGCAGCTCAGGTGGGCGGGGAGGGGACGGGGCCGGGGCAGCTCAGGTGGGCGGGGAGGGGACGGGCGGGGGAGGGGGGGCCGGG	p.Gln1431_Arg1433del	splice_donor conservative_inframe_deletion splice_region intron	Exon 24 of 36	ENSP00000368678.2	O00468-6
	AGRN	ENST00000651234.1		c.3975_3983+74delGCAGCTCAGGTGGGCGGGGAGGGGACGGGGCCGGGGCAGCTCAGGTGGGCGGGGAGGGGACGGGCGGGGGAGGGGGGGCCGGG	p.Gln1326_Arg1328del	splice_donor conservative_inframe_deletion splice_region intron	Exon 23 of 38	ENSP00000499046.1	A0A494C1I6
	AGRN	ENST00000652369.2		c.3975_3983+74delGCAGCTCAGGTGGGCGGGGAGGGGACGGGGCCGGGGCAGCTCAGGTGGGCGGGGAGGGGACGGGCGGGGGAGGGGGGGCCGGG	p.Gln1326_Arg1328del	splice_donor conservative_inframe_deletion splice_region intron	Exon 23 of 35	ENSP00000498543.1	A0A494C0G5

Frequencies

GnomAD3 genomes AF: 0.00742 AC: 1047 AN: 141056 Hom.: 8 Cov.: 24

Gnomad AFR AF: 0.0285

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00326

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: 0.0000601

Gnomad OTH AF: 0.00255

GnomAD2 exomes AF: 0.00151 AC: 233 AN: 154216 AF XY: 0.00131

Gnomad AFR exome AF: 0.0266

Gnomad AMR exome AF: 0.000818

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000168

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000102

Gnomad OTH exome AF: 0.000923

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000752 AC: 1054 AN: 1402258 Hom.: 13 AF XY: 0.000625 AC XY: 433 AN XY: 692774

African (AFR) AF: 0.0270 AC: 840 AN: 31072

American (AMR) AF: 0.00123 AC: 46 AN: 37404

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25080

East Asian (EAS) AF: 0.0000553 AC: 2 AN: 36134

South Asian (SAS) AF: 0.000101 AC: 8 AN: 79198

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47444

Middle Eastern (MID) AF: 0.00222 AC: 9 AN: 4054

European-Non Finnish (NFE) AF: 0.0000314 AC: 34 AN: 1084024

Other (OTH) AF: 0.00199 AC: 115 AN: 57848

GnomAD4 genome AF: 0.00742 AC: 1047 AN: 141150 Hom.: 8 Cov.: 24 AF XY: 0.00751 AC XY: 514 AN XY: 68440

African (AFR) AF: 0.0284 AC: 993 AN: 34928

American (AMR) AF: 0.00318 AC: 45 AN: 14142

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3388

East Asian (EAS) AF: 0.00 AC: 0 AN: 4880

South Asian (SAS) AF: 0.00 AC: 0 AN: 4488

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.0000601 AC: 4 AN: 66566

Other (OTH) AF: 0.00253 AC: 5 AN: 1980

Alfa AF: 0.000669 Hom.: 1

Asia WGS AF: 0.00173 AC: 6 AN: 3474

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.2
Mutation Taster		=57/143	disease causing (long InDel)

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1553177542;

hg19: chr1-984430;