rs6657048

Variant names:

• chr1-1022260-C-T
• rs6657048
• NM_198576.4:c.261C>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_198576.4(AGRN):​c.261C>T​(p.Asp87Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0162 in 1,613,184 control chromosomes in the GnomAD database, including 425 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.029 (123 hom., cov: 34)
  • Exomes 𝑓: 0.015 (302 hom.)
• Consequence: AGRN NM_198576.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -2.21
• Publications: 6 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 1-1022260-C-T is Benign according to our data. Variant chr1-1022260-C-T is described in ClinVar as Benign. ClinVar VariationId is 128296.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.21 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0665 is higher than 0.05.

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.261C>T	p.Asp87Asp	synonymous	Exon 2 of 36	NP_940978.2
	AGRN	NM_001305275.2		c.261C>T	p.Asp87Asp	synonymous	Exon 2 of 39	NP_001292204.1	O00468-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGRN	ENST00000379370.7	TSL:1 MANE Select	c.261C>T	p.Asp87Asp	synonymous	Exon 2 of 36	ENSP00000368678.2	O00468-6
	AGRN	ENST00000620552.4	TSL:5	c.-154C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 39	ENSP00000484607.1	A0A087X208
	AGRN	ENST00000620552.4	TSL:5	c.-154C>T		5_prime_UTR	Exon 2 of 39	ENSP00000484607.1	A0A087X208

Frequencies

GnomAD3 genomes AF: 0.0288 AC: 4384 AN: 152188 Hom.: 123 Cov.: 34

Gnomad AFR AF: 0.0687

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.0108

Gnomad ASJ AF: 0.0187

Gnomad EAS AF: 0.00538

Gnomad SAS AF: 0.0356

Gnomad FIN AF: 0.00443

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0146

Gnomad OTH AF: 0.0287

GnomAD2 exomes AF: 0.0181 AC: 4549 AN: 250898 AF XY: 0.0187

Gnomad AFR exome AF: 0.0726

Gnomad AMR exome AF: 0.00633

Gnomad ASJ exome AF: 0.0168

Gnomad EAS exome AF: 0.00413

Gnomad FIN exome AF: 0.00508

Gnomad NFE exome AF: 0.0143

Gnomad OTH exome AF: 0.0135

GnomAD4 exome AF: 0.0148 AC: 21676 AN: 1460878 Hom.: 302 Cov.: 33 AF XY: 0.0155 AC XY: 11265 AN XY: 726746

African (AFR) AF: 0.0725 AC: 2427 AN: 33480

American (AMR) AF: 0.00729 AC: 326 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0187 AC: 489 AN: 26136

East Asian (EAS) AF: 0.00189 AC: 75 AN: 39696

South Asian (SAS) AF: 0.0363 AC: 3127 AN: 86258

European-Finnish (FIN) AF: 0.00644 AC: 338 AN: 52468

Middle Eastern (MID) AF: 0.0243 AC: 140 AN: 5768

European-Non Finnish (NFE) AF: 0.0124 AC: 13743 AN: 1111970

Other (OTH) AF: 0.0167 AC: 1011 AN: 60378

GnomAD4 genome AF: 0.0288 AC: 4387 AN: 152306 Hom.: 123 Cov.: 34 AF XY: 0.0281 AC XY: 2092 AN XY: 74470

African (AFR) AF: 0.0686 AC: 2849 AN: 41544

American (AMR) AF: 0.0108 AC: 165 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0187 AC: 65 AN: 3470

East Asian (EAS) AF: 0.00520 AC: 27 AN: 5188

South Asian (SAS) AF: 0.0358 AC: 173 AN: 4830

European-Finnish (FIN) AF: 0.00443 AC: 47 AN: 10620

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0146 AC: 993 AN: 68028

Other (OTH) AF: 0.0279 AC: 59 AN: 2116

Alfa AF: 0.0199 Hom.: 83

Bravo AF: 0.0307

Asia WGS AF: 0.0190 AC: 67 AN: 3478

EpiCase AF: 0.0172

EpiControl AF: 0.0154

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	1	Congenital myasthenic syndrome 8 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	0.59
DANN	Benign	0.87
PhyloP100		-2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
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: rs6657048; hg19: chr1-957640; COSMIC: COSV65070021;