rs2275812

Variant names:

• chr1-1050066-G-T
• rs2275812
• NM_198576.4:c.4879+29G>T

Your query was ambiguous. Multiple possible variants found:

• chr1-1050066-G-T
• chr1-1050066-G-A
• chr1-1050066-G-C

Variant summary

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

The NM_198576.4(AGRN):​c.4879+29G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.437 in 1,355,900 control chromosomes in the GnomAD database, including 122,381 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.35 (9412 hom., cov: 28)
  • Exomes 𝑓: 0.45 (112969 hom.)
• Consequence: AGRN NM_198576.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.24
• Publications: 7 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 1-1050066-G-T is Benign according to our data. Variant chr1-1050066-G-T is described in ClinVar as Benign. ClinVar VariationId is 263191.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.451 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.4879+29G>T		intron	N/A	NP_940978.2
	AGRN	NM_001305275.2		c.4879+29G>T		intron	N/A	NP_001292204.1	O00468-1
	AGRN	NM_001364727.2		c.4564+29G>T		intron	N/A	NP_001351656.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGRN	ENST00000379370.7	TSL:1 MANE Select	c.4879+29G>T		intron	N/A	ENSP00000368678.2	O00468-6
	AGRN	ENST00000651234.1		c.4564+29G>T		intron	N/A	ENSP00000499046.1	A0A494C1I6
	AGRN	ENST00000652369.2		c.4564+29G>T		intron	N/A	ENSP00000498543.1	A0A494C0G5

Frequencies

GnomAD3 genomes AF: 0.352 AC: 49304 AN: 140174 Hom.: 9412 Cov.: 28

Gnomad AFR AF: 0.110

Gnomad AMI AF: 0.523

Gnomad AMR AF: 0.449

Gnomad ASJ AF: 0.450

Gnomad EAS AF: 0.168

Gnomad SAS AF: 0.469

Gnomad FIN AF: 0.415

Gnomad MID AF: 0.474

Gnomad NFE AF: 0.453

Gnomad OTH AF: 0.380

GnomAD2 exomes AF: 0.415 AC: 53611 AN: 129156 AF XY: 0.422

Gnomad AFR exome AF: 0.102

Gnomad AMR exome AF: 0.438

Gnomad ASJ exome AF: 0.440

Gnomad EAS exome AF: 0.155

Gnomad FIN exome AF: 0.419

Gnomad NFE exome AF: 0.459

Gnomad OTH exome AF: 0.419

GnomAD4 exome AF: 0.446 AC: 542767 AN: 1215632 Hom.: 112969 Cov.: 22 AF XY: 0.445 AC XY: 268308 AN XY: 602956

African (AFR) AF: 0.0991 AC: 2498 AN: 25202

American (AMR) AF: 0.410 AC: 13603 AN: 33208

Ashkenazi Jewish (ASJ) AF: 0.437 AC: 9993 AN: 22876

East Asian (EAS) AF: 0.130 AC: 4325 AN: 33266

South Asian (SAS) AF: 0.442 AC: 32280 AN: 73072

European-Finnish (FIN) AF: 0.388 AC: 16964 AN: 43762

Middle Eastern (MID) AF: 0.441 AC: 1611 AN: 3650

European-Non Finnish (NFE) AF: 0.474 AC: 440316 AN: 929608

Other (OTH) AF: 0.415 AC: 21177 AN: 50988

GnomAD4 genome AF: 0.352 AC: 49310 AN: 140268 Hom.: 9412 Cov.: 28 AF XY: 0.353 AC XY: 24135 AN XY: 68414

African (AFR) AF: 0.110 AC: 4066 AN: 37114

American (AMR) AF: 0.449 AC: 6366 AN: 14178

Ashkenazi Jewish (ASJ) AF: 0.450 AC: 1490 AN: 3312

East Asian (EAS) AF: 0.169 AC: 620 AN: 3678

South Asian (SAS) AF: 0.468 AC: 2088 AN: 4462

European-Finnish (FIN) AF: 0.415 AC: 4094 AN: 9866

Middle Eastern (MID) AF: 0.476 AC: 136 AN: 286

European-Non Finnish (NFE) AF: 0.453 AC: 29256 AN: 64562

Other (OTH) AF: 0.383 AC: 757 AN: 1974

Alfa AF: 0.182 Hom.: 293

ClinVar

ClinVar submissions

Significance: 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	-0.89
CADD	Benign	0.20
DANN	Benign	0.55
PhyloP100		-1.2
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs2275812;

hg19: chr1-985446;

COSMIC: COSV65067816;

COSMIC: COSV65067816;