rs148518738

chr1-1050545-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2 BP4_Strong BP6 BS1

The NM_198576.4(AGRN):c.5095C>T(p.Arg1699Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000475 in 1,612,598 control chromosomes in the GnomAD database, including 1 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1699H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0024 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00028 (1 hom.)
• Consequence: AGRN NM_198576.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -0.211

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

Verdict is Benign. Variant got -7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.010977954).
• BP6: Variant 1-1050545-C-T is Benign according to our data. Variant chr1-1050545-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 541191.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00237 (361/152272) while in subpopulation AFR AF= 0.0084 (349/41538). AF 95% confidence interval is 0.00768. There are 0 homozygotes in gnomad4. There are 157 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AGRN	NM_198576.4	c.5095C>T	p.Arg1699Cys	missense_variant	29/36	ENST00000379370.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AGRN	ENST00000379370.7	c.5095C>T	p.Arg1699Cys	missense_variant	29/36	1	NM_198576.4	P1
AGRN	ENST00000651234.1	c.4780C>T	p.Arg1594Cys	missense_variant	28/38
AGRN	ENST00000652369.1	c.4780C>T	p.Arg1594Cys	missense_variant	28/35
AGRN	ENST00000620552.4	c.4681C>T	p.Arg1561Cys	missense_variant	29/39	5

Frequencies

GnomAD3 genomes AF: 0.00237 AC: 361 AN: 152154 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00843

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000654

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: 0.00

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000629 AC: 156 AN: 247842 Hom.: 1 AF XY: 0.000527 AC XY: 71 AN XY: 134780

Gnomad AFR exome AF: 0.00887

Gnomad AMR exome AF: 0.0000580

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000556

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000448

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.000277 AC: 405 AN: 1460326 Hom.: 1 Cov.: 35 AF XY: 0.000249 AC XY: 181 AN XY: 726518

Gnomad4 AFR exome AF: 0.0105

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000989

Gnomad4 OTH exome AF: 0.000414

GnomAD4 genome AF: 0.00237 AC: 361 AN: 152272 Hom.: 0 Cov.: 33 AF XY: 0.00211 AC XY: 157 AN XY: 74464

Gnomad4 AFR AF: 0.00840

Gnomad4 AMR AF: 0.000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.00154 Hom.: 1

Bravo AF: 0.00254

ESP6500AA AF: 0.0109 AC: 48

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000750 AC: 91

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	AGRN: BP4, BS1 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 18, 2020	- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 03, 2022

The c.5095C>T (p.R1699C) alteration is located in exon 29 (coding exon 29) of the AGRN gene. This alteration results from a C to T substitution at nucleotide position 5095, causing the arginine (R) at amino acid position 1699 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Congenital myasthenic syndrome 8 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 23, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.41
Cadd	Benign	18
Dann	Benign	0.97
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.26	N
LIST_S2	Uncertain	0.97	D;D
MetaRNN	Benign	0.011	T;T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	1.5	L;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-1.2	N;.
REVEL	Benign	0.23
Sift	Benign	0.14	T;.
Sift4G	Benign	0.17	T;T
Vest4		0.29
MVP		0.79
MPC		0.44
ClinPred		0.026	T
GERP RS		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.2
gMVP		0.60

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: rs148518738; hg19: chr1-985925; COSMIC: COSV104688626; COSMIC: COSV104688626;