rs10267

Variant names:

• chr1-1047614-T-C
• rs10267
• NM_198576.4:c.3558T>C

Your query was ambiguous. Multiple possible variants found:

• chr1-1047614-T-C
• chr1-1047614-T-A
• chr1-1047614-T-G

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.3558T>C​(p.Phe1186Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.907 in 1,612,940 control chromosomes in the GnomAD database, including 669,418 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.82 (53400 hom., cov: 35)
  • Exomes 𝑓: 0.92 (616018 hom.)
• Consequence: AGRN NM_198576.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 2.15
• Publications: 17 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=-0.63).
• BP6: Variant 1-1047614-T-C is Benign according to our data. Variant chr1-1047614-T-C is described in ClinVar as Benign. ClinVar VariationId is 128302.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.15 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.976 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.3558T>C	p.Phe1186Phe	synonymous	Exon 21 of 36	NP_940978.2
	AGRN	NM_001305275.2		c.3558T>C	p.Phe1186Phe	synonymous	Exon 21 of 39	NP_001292204.1	O00468-1
	AGRN	NM_001364727.2		c.3243T>C	p.Phe1081Phe	synonymous	Exon 20 of 36	NP_001351656.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGRN	ENST00000379370.7	TSL:1 MANE Select	c.3558T>C	p.Phe1186Phe	synonymous	Exon 21 of 36	ENSP00000368678.2	O00468-6
	AGRN	ENST00000651234.1		c.3243T>C	p.Phe1081Phe	synonymous	Exon 20 of 38	ENSP00000499046.1	A0A494C1I6
	AGRN	ENST00000652369.2		c.3243T>C	p.Phe1081Phe	synonymous	Exon 20 of 35	ENSP00000498543.1	A0A494C0G5

Frequencies

GnomAD3 genomes AF: 0.820 AC: 124694 AN: 152140 Hom.: 53403 Cov.: 35

Gnomad AFR AF: 0.538

Gnomad AMI AF: 0.986

Gnomad AMR AF: 0.896

Gnomad ASJ AF: 0.924

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.957

Gnomad FIN AF: 0.958

Gnomad MID AF: 0.879

Gnomad NFE AF: 0.920

Gnomad OTH AF: 0.846

GnomAD2 exomes AF: 0.908 AC: 227622 AN: 250598 AF XY: 0.916

Gnomad AFR exome AF: 0.525

Gnomad AMR exome AF: 0.939

Gnomad ASJ exome AF: 0.923

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 0.953

Gnomad NFE exome AF: 0.917

Gnomad OTH exome AF: 0.908

GnomAD4 exome AF: 0.916 AC: 1337920 AN: 1460682 Hom.: 616018 Cov.: 92 AF XY: 0.918 AC XY: 667056 AN XY: 726632

African (AFR) AF: 0.516 AC: 17271 AN: 33480

American (AMR) AF: 0.933 AC: 41707 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.920 AC: 24044 AN: 26136

East Asian (EAS) AF: 1.00 AC: 39685 AN: 39700

South Asian (SAS) AF: 0.952 AC: 82130 AN: 86258

European-Finnish (FIN) AF: 0.951 AC: 49677 AN: 52244

Middle Eastern (MID) AF: 0.864 AC: 4986 AN: 5768

European-Non Finnish (NFE) AF: 0.921 AC: 1024039 AN: 1111990

Other (OTH) AF: 0.901 AC: 54381 AN: 60384

GnomAD4 genome AF: 0.819 AC: 124724 AN: 152258 Hom.: 53400 Cov.: 35 AF XY: 0.825 AC XY: 61395 AN XY: 74446

African (AFR) AF: 0.537 AC: 22307 AN: 41512

American (AMR) AF: 0.896 AC: 13715 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.924 AC: 3207 AN: 3472

East Asian (EAS) AF: 0.999 AC: 5174 AN: 5178

South Asian (SAS) AF: 0.956 AC: 4621 AN: 4834

European-Finnish (FIN) AF: 0.958 AC: 10178 AN: 10624

Middle Eastern (MID) AF: 0.877 AC: 256 AN: 292

European-Non Finnish (NFE) AF: 0.920 AC: 62575 AN: 68016

Other (OTH) AF: 0.848 AC: 1792 AN: 2114

Alfa AF: 0.878 Hom.: 34847

Bravo AF: 0.800

Asia WGS AF: 0.947 AC: 3292 AN: 3478

EpiCase AF: 0.915

EpiControl AF: 0.907

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Congenital myasthenic syndrome 8 (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	6.6
DANN	Benign	0.32
PhyloP100		2.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs10267; hg19: chr1-982994; COSMIC: COSV65071416; COSMIC: COSV65071416;