rs34708466

Variant names:

• chr1-1051248-C-T
• rs34708466
• NM_198576.4:c.5254-5C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-1051248-C-T
• chr1-1051248-C-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_198576.4(AGRN):​c.5254-5C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00369 in 1,580,848 control chromosomes in the GnomAD database, including 16 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0024 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0038 (14 hom.)
• Consequence: AGRN NM_198576.4 splice_region, intron
• Scores: Splicing: ADA: 0.00001593
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.0540
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 1-1051248-C-T is Benign according to our data. Variant chr1-1051248-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 474146.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0024 (366/152280) while in subpopulation NFE AF = 0.00462 (314/68000). AF 95% confidence interval is 0.0042. There are 2 homozygotes in GnomAd4. There are 150 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR,AD gene

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.5254-5C>T		splice_region intron	N/A	NP_940978.2
	AGRN	NM_001305275.2		c.5266-5C>T		splice_region intron	N/A	NP_001292204.1	O00468-1
	AGRN	NM_001364727.2		c.4951-5C>T		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.5254-5C>T		splice_region intron	N/A	ENSP00000368678.2	O00468-6
	AGRN	ENST00000651234.1		c.4951-5C>T		splice_region intron	N/A	ENSP00000499046.1	A0A494C1I6
	AGRN	ENST00000652369.2		c.4939-5C>T		splice_region intron	N/A	ENSP00000498543.1	A0A494C0G5

Frequencies

GnomAD3 genomes AF: 0.00241 AC: 366 AN: 152162 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000797

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000847

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00462

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00226 AC: 441 AN: 194880 AF XY: 0.00214

Gnomad AFR exome AF: 0.000518

Gnomad AMR exome AF: 0.000546

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00170

Gnomad NFE exome AF: 0.00444

Gnomad OTH exome AF: 0.00180

GnomAD4 exome AF: 0.00383 AC: 5469 AN: 1428568 Hom.: 14 Cov.: 37 AF XY: 0.00361 AC XY: 2553 AN XY: 707624

African (AFR) AF: 0.000761 AC: 25 AN: 32846

American (AMR) AF: 0.000572 AC: 23 AN: 40234

Ashkenazi Jewish (ASJ) AF: 0.0000392 AC: 1 AN: 25512

East Asian (EAS) AF: 0.00 AC: 0 AN: 37960

South Asian (SAS) AF: 0.000368 AC: 30 AN: 81514

European-Finnish (FIN) AF: 0.00169 AC: 83 AN: 49044

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5584

European-Non Finnish (NFE) AF: 0.00462 AC: 5069 AN: 1096732

Other (OTH) AF: 0.00402 AC: 238 AN: 59142

GnomAD4 genome AF: 0.00240 AC: 366 AN: 152280 Hom.: 2 Cov.: 33 AF XY: 0.00201 AC XY: 150 AN XY: 74456

African (AFR) AF: 0.000794 AC: 33 AN: 41550

American (AMR) AF: 0.000588 AC: 9 AN: 15304

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.000847 AC: 9 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00462 AC: 314 AN: 68000

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.00288 Hom.: 1

Bravo AF: 0.00247

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely 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	-0.77
CADD	Benign	2.9
DANN	Benign	0.75
PhyloP100		0.054
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000016
dbscSNV1_RF	Benign	0.0
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: rs34708466; hg19: chr1-986628;