chr1-1049467-G-C

Variant names:

• chr1-1049467-G-C
• rs112917612
• NM_198576.4:c.4514+16G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001305275.2(AGRN):​c.4514+16G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.017 in 1,600,510 control chromosomes in the GnomAD database, including 1,445 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.059 (732 hom., cov: 32)
  • Exomes 𝑓: 0.013 (713 hom.)
• Consequence: AGRN NM_001305275.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.863
• Publications: 3 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=-0.84).
• BP6: Variant 1-1049467-G-C is Benign according to our data. Variant chr1-1049467-G-C is described in ClinVar as Benign. ClinVar VariationId is 263186.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.185 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001305275.2. 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.4514+16G>C		intron	N/A	NP_940978.2
	AGRN	NM_001305275.2		c.4514+16G>C		intron	N/A	NP_001292204.1
	AGRN	NM_001364727.2		c.4199+16G>C		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.4514+16G>C		intron	N/A	ENSP00000368678.2
	AGRN	ENST00000651234.1		c.4199+16G>C		intron	N/A	ENSP00000499046.1
	AGRN	ENST00000652369.2		c.4199+16G>C		intron	N/A	ENSP00000498543.1

Frequencies

GnomAD3 genomes AF: 0.0592 AC: 8999 AN: 152058 Hom.: 728 Cov.: 32

Gnomad AFR AF: 0.188

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.0281

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00642

Gnomad FIN AF: 0.000659

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.00921

Gnomad OTH AF: 0.0507

GnomAD2 exomes AF: 0.0203 AC: 4813 AN: 236558 AF XY: 0.0162

Gnomad AFR exome AF: 0.194

Gnomad AMR exome AF: 0.0154

Gnomad ASJ exome AF: 0.00494

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00126

Gnomad NFE exome AF: 0.00944

Gnomad OTH exome AF: 0.0150

GnomAD4 exome AF: 0.0125 AC: 18123 AN: 1448334 Hom.: 713 Cov.: 43 AF XY: 0.0118 AC XY: 8532 AN XY: 721038

African (AFR) AF: 0.195 AC: 6533 AN: 33454

American (AMR) AF: 0.0171 AC: 762 AN: 44648

Ashkenazi Jewish (ASJ) AF: 0.00529 AC: 138 AN: 26102

East Asian (EAS) AF: 0.00 AC: 0 AN: 39670

South Asian (SAS) AF: 0.00410 AC: 353 AN: 86130

European-Finnish (FIN) AF: 0.00142 AC: 58 AN: 40800

Middle Eastern (MID) AF: 0.0343 AC: 198 AN: 5766

European-Non Finnish (NFE) AF: 0.00797 AC: 8858 AN: 1111530

Other (OTH) AF: 0.0203 AC: 1223 AN: 60234

GnomAD4 genome AF: 0.0594 AC: 9041 AN: 152176 Hom.: 732 Cov.: 32 AF XY: 0.0570 AC XY: 4242 AN XY: 74406

African (AFR) AF: 0.188 AC: 7811 AN: 41486

American (AMR) AF: 0.0280 AC: 428 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00461 AC: 16 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5156

South Asian (SAS) AF: 0.00663 AC: 32 AN: 4826

European-Finnish (FIN) AF: 0.000659 AC: 7 AN: 10624

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.00921 AC: 626 AN: 67990

Other (OTH) AF: 0.0502 AC: 106 AN: 2112

Alfa AF: 0.00242 Hom.: 1

Bravo AF: 0.0683

Asia WGS AF: 0.0160 AC: 56 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	7.3
DANN	Benign	0.29
PhyloP100		0.86
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs112917612; hg19: chr1-984847; COSMIC: COSV65070069; COSMIC: COSV65070069;