chr1-1022518-G-T

Variant names:

• chr1-1022518-G-T
• rs2799064
• NM_198576.4:c.463+56G>T

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.463+56G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.345 in 1,557,668 control chromosomes in the GnomAD database, including 94,257 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.34 (9382 hom., cov: 33)
  • Exomes 𝑓: 0.34 (84875 hom.)
• Consequence: AGRN NM_198576.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.495

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]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 1-1022518-G-T is Benign according to our data. Variant chr1-1022518-G-T is described in ClinVar as [Benign]. Clinvar id is 677944.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-1022518-G-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.357 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGRN	NM_198576.4	c.463+56G>T		intron_variant	Intron 2 of 35	ENST00000379370.7	NP_940978.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGRN	ENST00000379370.7	c.463+56G>T		intron_variant	Intron 2 of 35	1	NM_198576.4	ENSP00000368678.2
AGRN	ENST00000620552.4	c.49+56G>T		intron_variant	Intron 2 of 38	5		ENSP00000484607.1

Frequencies

GnomAD3 genomes AF: 0.345 AC: 52411 AN: 151886 Hom.: 9381 Cov.: 33

Gnomad AFR AF: 0.359

Gnomad AMI AF: 0.389

Gnomad AMR AF: 0.251

Gnomad ASJ AF: 0.310

Gnomad EAS AF: 0.189

Gnomad SAS AF: 0.372

Gnomad FIN AF: 0.441

Gnomad MID AF: 0.301

Gnomad NFE AF: 0.355

Gnomad OTH AF: 0.329

GnomAD4 exome AF: 0.345 AC: 484392 AN: 1405664 Hom.: 84875 AF XY: 0.346 AC XY: 239948 AN XY: 693378

African (AFR) AF: 0.357 AC: 11530 AN: 32272

American (AMR) AF: 0.231 AC: 9384 AN: 40612

Ashkenazi Jewish (ASJ) AF: 0.313 AC: 7176 AN: 22890

East Asian (EAS) AF: 0.179 AC: 7024 AN: 39176

South Asian (SAS) AF: 0.364 AC: 28284 AN: 77762

European-Finnish (FIN) AF: 0.427 AC: 20849 AN: 48790

Middle Eastern (MID) AF: 0.290 AC: 1546 AN: 5340

European-Non Finnish (NFE) AF: 0.351 AC: 379199 AN: 1080832

Other (OTH) AF: 0.335 AC: 19400 AN: 57990

GnomAD4 genome AF: 0.345 AC: 52425 AN: 152004 Hom.: 9382 Cov.: 33 AF XY: 0.347 AC XY: 25763 AN XY: 74274

African (AFR) AF: 0.359 AC: 14879 AN: 41442

American (AMR) AF: 0.250 AC: 3824 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.310 AC: 1075 AN: 3468

East Asian (EAS) AF: 0.189 AC: 978 AN: 5166

South Asian (SAS) AF: 0.372 AC: 1792 AN: 4822

European-Finnish (FIN) AF: 0.441 AC: 4660 AN: 10562

Middle Eastern (MID) AF: 0.293 AC: 86 AN: 294

European-Non Finnish (NFE) AF: 0.355 AC: 24090 AN: 67942

Other (OTH) AF: 0.326 AC: 687 AN: 2110

Alfa AF: 0.348 Hom.: 13446

Bravo AF: 0.329

Asia WGS AF: 0.284 AC: 989 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 16, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	2.7
DANN	Benign	0.41
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

Publications

LitVar

Other links and lift over

dbSNP: rs2799064; hg19: chr1-957898; COSMIC: COSV65071508;