rs9697293

Positions:

• chr1-1045751-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_198576.4(AGRN):​c.2555A>G​(p.Gln852Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00785 in 1,613,344 control chromosomes in the GnomAD database, including 260 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (108 hom., cov: 33)
  • Exomes 𝑓: 0.0061 (152 hom.)
• Consequence: AGRN NM_198576.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.151

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007983774).
• BP6: Variant 1-1045751-A-G is Benign according to our data. Variant chr1-1045751-A-G is described in ClinVar as [Benign]. Clinvar id is 263173.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-1045751-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0692 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AGRN	NM_198576.4	c.2555A>G	p.Gln852Arg	missense_variant	15/36	ENST00000379370.7	NP_940978.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AGRN	ENST00000379370.7	c.2555A>G	p.Gln852Arg	missense_variant	15/36	1	NM_198576.4	ENSP00000368678.2

Frequencies

GnomAD3 genomes AF: 0.0246 AC: 3749 AN: 152132 Hom.: 106 Cov.: 33

Gnomad AFR AF: 0.0712

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0115

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.0316

Gnomad SAS AF: 0.00995

Gnomad FIN AF: 0.0190

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00247

Gnomad OTH AF: 0.0138

GnomAD3 exomes AF: 0.0123 AC: 3075 AN: 250798 Hom.: 58 AF XY: 0.0113 AC XY: 1534 AN XY: 135782

Gnomad AFR exome AF: 0.0733

Gnomad AMR exome AF: 0.00642

Gnomad ASJ exome AF: 0.00587

Gnomad EAS exome AF: 0.0279

Gnomad SAS exome AF: 0.00853

Gnomad FIN exome AF: 0.0197

Gnomad NFE exome AF: 0.00306

Gnomad OTH exome AF: 0.00946

GnomAD4 exome AF: 0.00609 AC: 8902 AN: 1461094 Hom.: 152 Cov.: 39 AF XY: 0.00599 AC XY: 4351 AN XY: 726876

Gnomad4 AFR exome AF: 0.0737

Gnomad4 AMR exome AF: 0.00675

Gnomad4 ASJ exome AF: 0.00551

Gnomad4 EAS exome AF: 0.0303

Gnomad4 SAS exome AF: 0.00936

Gnomad4 FIN exome AF: 0.0182

Gnomad4 NFE exome AF: 0.00211

Gnomad4 OTH exome AF: 0.0101

GnomAD4 genome AF: 0.0247 AC: 3763 AN: 152250 Hom.: 108 Cov.: 33 AF XY: 0.0253 AC XY: 1883 AN XY: 74442

Gnomad4 AFR AF: 0.0713

Gnomad4 AMR AF: 0.0115

Gnomad4 ASJ AF: 0.00375

Gnomad4 EAS AF: 0.0315

Gnomad4 SAS AF: 0.0102

Gnomad4 FIN AF: 0.0190

Gnomad4 NFE AF: 0.00247

Gnomad4 OTH AF: 0.0137

Alfa AF: 0.00800 Hom.: 27

Bravo AF: 0.0255

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.0679 AC: 299

ESP6500EA AF: 0.00233 AC: 20

ExAC AF: 0.0137 AC: 1663

Asia WGS AF: 0.0260 AC: 90 AN: 3478

EpiCase AF: 0.00229

EpiControl AF: 0.00279

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 31, 2016	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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Congenital myasthenic syndrome 8 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 24, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	0.54
DANN	Benign	0.64
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.021	N
LIST_S2	Benign	0.63	T;T
MetaRNN	Benign	0.0080	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.070	N;.
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.39	N;.
REVEL	Benign	0.036
Sift	Benign	0.37	T;.
Sift4G	Benign	0.84	T;T
Vest4		0.10
MPC		0.21
ClinPred		0.000018	T
GERP RS		-0.62
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.17

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

Publications

LitVar

Other links and lift over

dbSNP: rs9697293; hg19: chr1-981131; COSMIC: COSV65071007; COSMIC: COSV65071007;