chr1-1045568-C-T

Variant names:

• chr1-1045568-C-T
• rs183108359
• NM_198576.4:c.2536+45C>T

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.2536+45C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00879 in 1,607,566 control chromosomes in the GnomAD database, including 234 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0066 (12 hom., cov: 34)
  • Exomes 𝑓: 0.0090 (222 hom.)
• Consequence: AGRN NM_198576.4 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.506
• Publications: 2 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=-0.82).
• BP6: Variant 1-1045568-C-T is Benign according to our data. Variant chr1-1045568-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 263171.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00662 (1006/152026) while in subpopulation SAS AF = 0.0408 (197/4830). AF 95% confidence interval is 0.0361. There are 12 homozygotes in GnomAd4. There are 546 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 12 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGRN	NM_198576.4	MANE Select	c.2536+45C>T		intron	N/A	NP_940978.2
	AGRN	NM_001305275.2		c.2536+45C>T		intron	N/A	NP_001292204.1
	AGRN	NM_001364727.2		c.2221+45C>T		intron	N/A	NP_001351656.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGRN	ENST00000379370.7	TSL:1 MANE Select	c.2536+45C>T		intron	N/A	ENSP00000368678.2
	AGRN	ENST00000651234.1		c.2221+45C>T		intron	N/A	ENSP00000499046.1
	AGRN	ENST00000652369.2		c.2221+45C>T		intron	N/A	ENSP00000498543.1

Frequencies

GnomAD3 genomes AF: 0.00665 AC: 1010 AN: 151908 Hom.: 13 Cov.: 34

Gnomad AFR AF: 0.00168

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00628

Gnomad ASJ AF: 0.0397

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0414

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.00670

Gnomad OTH AF: 0.0120

GnomAD2 exomes AF: 0.0114 AC: 2760 AN: 242968 AF XY: 0.0133

Gnomad AFR exome AF: 0.00201

Gnomad AMR exome AF: 0.00510

Gnomad ASJ exome AF: 0.0379

Gnomad EAS exome AF: 0.0000555

Gnomad FIN exome AF: 0.000651

Gnomad NFE exome AF: 0.00702

Gnomad OTH exome AF: 0.0134

GnomAD4 exome AF: 0.00901 AC: 13118 AN: 1455540 Hom.: 222 Cov.: 34 AF XY: 0.0103 AC XY: 7475 AN XY: 723322

African (AFR) AF: 0.00159 AC: 53 AN: 33398

American (AMR) AF: 0.00513 AC: 228 AN: 44442

Ashkenazi Jewish (ASJ) AF: 0.0384 AC: 1000 AN: 26070

East Asian (EAS) AF: 0.0000506 AC: 2 AN: 39490

South Asian (SAS) AF: 0.0435 AC: 3747 AN: 86054

European-Finnish (FIN) AF: 0.00105 AC: 54 AN: 51266

Middle Eastern (MID) AF: 0.0481 AC: 277 AN: 5760

European-Non Finnish (NFE) AF: 0.00631 AC: 7001 AN: 1108952

Other (OTH) AF: 0.0126 AC: 756 AN: 60108

GnomAD4 genome AF: 0.00662 AC: 1006 AN: 152026 Hom.: 12 Cov.: 34 AF XY: 0.00735 AC XY: 546 AN XY: 74324

African (AFR) AF: 0.00167 AC: 69 AN: 41302

American (AMR) AF: 0.00627 AC: 96 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0397 AC: 138 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.0408 AC: 197 AN: 4830

European-Finnish (FIN) AF: 0.00104 AC: 11 AN: 10618

Middle Eastern (MID) AF: 0.0476 AC: 14 AN: 294

European-Non Finnish (NFE) AF: 0.00670 AC: 456 AN: 68018

Other (OTH) AF: 0.0119 AC: 25 AN: 2108

Alfa AF: 0.00984 Hom.: 5

Bravo AF: 0.00583

Asia WGS AF: 0.0130 AC: 45 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.8
DANN	Benign	0.47
PhyloP100		-0.51
Mutation Taster		=100/0	polymorphism (auto)

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: rs183108359; hg19: chr1-980948;