1-1041249-C-T

Variant names:

• chr1-1041249-C-T
• rs113789806
• NM_198576.4:c.804C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001305275.2(AGRN):​c.804C>T​(p.Ala268Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00845 in 1,496,312 control chromosomes in the GnomAD database, including 746 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A268A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.043 (410 hom., cov: 31)
  • Exomes 𝑓: 0.0046 (336 hom.)
• Consequence: AGRN NM_001305275.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.0480
• Publications: 1 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 1-1041249-C-T is Benign according to our data. Variant chr1-1041249-C-T is described in ClinVar as Benign. ClinVar VariationId is 128320.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.048 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.141 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.804C>T	p.Ala268Ala	synonymous	Exon 5 of 36	NP_940978.2
	AGRN	NM_001305275.2		c.804C>T	p.Ala268Ala	synonymous	Exon 5 of 39	NP_001292204.1
	AGRN	NM_001364727.2		c.489C>T	p.Ala163Ala	synonymous	Exon 4 of 36	NP_001351656.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGRN	ENST00000379370.7	TSL:1 MANE Select	c.804C>T	p.Ala268Ala	synonymous	Exon 5 of 36	ENSP00000368678.2
	AGRN	ENST00000651234.1		c.489C>T	p.Ala163Ala	synonymous	Exon 4 of 38	ENSP00000499046.1
	AGRN	ENST00000652369.2		c.489C>T	p.Ala163Ala	synonymous	Exon 4 of 35	ENSP00000498543.1

Frequencies

GnomAD3 genomes AF: 0.0428 AC: 6498 AN: 151798 Hom.: 410 Cov.: 31

Gnomad AFR AF: 0.144

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0226

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00152

Gnomad OTH AF: 0.0360

GnomAD2 exomes AF: 0.00599 AC: 605 AN: 100992 AF XY: 0.00504

Gnomad AFR exome AF: 0.152

Gnomad AMR exome AF: 0.0117

Gnomad ASJ exome AF: 0.00143

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000192

Gnomad NFE exome AF: 0.00147

Gnomad OTH exome AF: 0.00916

GnomAD4 exome AF: 0.00456 AC: 6126 AN: 1344406 Hom.: 336 Cov.: 33 AF XY: 0.00415 AC XY: 2751 AN XY: 663606

African (AFR) AF: 0.144 AC: 3862 AN: 26762

American (AMR) AF: 0.0133 AC: 419 AN: 31466

Ashkenazi Jewish (ASJ) AF: 0.00191 AC: 45 AN: 23514

East Asian (EAS) AF: 0.00 AC: 0 AN: 31166

South Asian (SAS) AF: 0.000633 AC: 48 AN: 75838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33230

Middle Eastern (MID) AF: 0.0145 AC: 79 AN: 5444

European-Non Finnish (NFE) AF: 0.000920 AC: 976 AN: 1061324

Other (OTH) AF: 0.0125 AC: 697 AN: 55662

GnomAD4 genome AF: 0.0429 AC: 6512 AN: 151906 Hom.: 410 Cov.: 31 AF XY: 0.0412 AC XY: 3056 AN XY: 74262

African (AFR) AF: 0.144 AC: 5972 AN: 41452

American (AMR) AF: 0.0225 AC: 344 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000828 AC: 4 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10514

Middle Eastern (MID) AF: 0.0137 AC: 4 AN: 292

European-Non Finnish (NFE) AF: 0.00152 AC: 103 AN: 67888

Other (OTH) AF: 0.0356 AC: 75 AN: 2108

Alfa AF: 0.0279 Hom.: 39

Bravo AF: 0.0498

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	1	Congenital myasthenic syndrome 8 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	7.7
DANN	Benign	0.96
PhyloP100		-0.048
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: rs113789806; hg19: chr1-976629;