rs148430436

Positions:

• chr1-1047589-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PM2 BP6_Very_Strong BS1

The NM_198576.4(AGRN):​c.3533G>A​(p.Arg1178Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00048 in 1,612,938 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1178W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0023 (0 hom., cov: 36)
  • Exomes 𝑓: 0.00029 (1 hom.)
• Consequence: AGRN NM_198576.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 4.18

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 -10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 1-1047589-G-A is Benign according to our data. Variant chr1-1047589-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 541190.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00234 (356/152344) while in subpopulation AFR AF= 0.00825 (343/41584). AF 95% confidence interval is 0.00753. There are 0 homozygotes in gnomad4. There are 156 alleles in male gnomad4 subpopulation. Median coverage is 36. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AGRN	NM_198576.4	c.3533G>A	p.Arg1178Gln	missense_variant	21/36	ENST00000379370.7	NP_940978.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AGRN	ENST00000379370.7	c.3533G>A	p.Arg1178Gln	missense_variant	21/36	1	NM_198576.4	ENSP00000368678.2

Frequencies

GnomAD3 genomes AF: 0.00234 AC: 356 AN: 152226 Hom.: 0 Cov.: 36

Gnomad AFR AF: 0.00827

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000958

GnomAD3 exomes AF: 0.000588 AC: 147 AN: 250166 Hom.: 1 AF XY: 0.000472 AC XY: 64 AN XY: 135660

Gnomad AFR exome AF: 0.00866

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000354

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000287 AC: 419 AN: 1460594 Hom.: 1 Cov.: 80 AF XY: 0.000255 AC XY: 185 AN XY: 726588

Gnomad4 AFR exome AF: 0.0106

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000288

Gnomad4 OTH exome AF: 0.000364

GnomAD4 genome AF: 0.00234 AC: 356 AN: 152344 Hom.: 0 Cov.: 36 AF XY: 0.00209 AC XY: 156 AN XY: 74482

Gnomad4 AFR AF: 0.00825

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000948

Alfa AF: 0.000677 Hom.: 2

Bravo AF: 0.00255

ESP6500AA AF: 0.0109 AC: 48

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000700 AC: 85

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 18, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	AGRN: PP3, BS1 -

Congenital myasthenic syndrome 8 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 23, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.50
CADD	Pathogenic	33
DANN	Uncertain	1.0
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.83	T;T
MetaRNN	Benign	0.011	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M;.
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.1	N;.
REVEL	Benign	0.13
Sift	Benign	0.096	T;.
Sift4G	Uncertain	0.056	T;T
Vest4		0.45
MVP		0.72
MPC		0.28
ClinPred		0.026	T
GERP RS		4.2
gMVP		0.59

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.67		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.67		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs148430436; hg19: chr1-982969; COSMIC: COSV65071258; COSMIC: COSV65071258;