chr1-1049746-G-C

Variant names:

• chr1-1049746-G-C
• rs199876002
• NM_198576.4:c.4695G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001305275.2(AGRN):​c.4695G>C​(p.Gln1565His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00135 in 1,579,520 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/20 in silico tools predict 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. Q1565R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0074 (7 hom., cov: 32)
  • Exomes 𝑓: 0.00071 (15 hom.)
• Consequence: AGRN NM_001305275.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.430
• Publications: 3 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: STRONG Submitted by: PanelApp Australia, 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 (MetaRNN=0.006070763).
• BP6: Variant 1-1049746-G-C is Benign according to our data. Variant chr1-1049746-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 387480.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 = 0.00736 (1111/151014) while in subpopulation AFR AF = 0.0259 (1062/41082). AF 95% confidence interval is 0.0246. There are 7 homozygotes in GnomAd4. There are 529 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001305275.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGRN	NM_198576.4	MANE Select	c.4695G>C	p.Gln1565His	missense	Exon 26 of 36	NP_940978.2
	AGRN	NM_001305275.2		c.4695G>C	p.Gln1565His	missense	Exon 26 of 39	NP_001292204.1
	AGRN	NM_001364727.2		c.4380G>C	p.Gln1460His	missense	Exon 25 of 36	NP_001351656.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGRN	ENST00000379370.7	TSL:1 MANE Select	c.4695G>C	p.Gln1565His	missense	Exon 26 of 36	ENSP00000368678.2
	AGRN	ENST00000651234.1		c.4380G>C	p.Gln1460His	missense	Exon 25 of 38	ENSP00000499046.1
	AGRN	ENST00000652369.2		c.4380G>C	p.Gln1460His	missense	Exon 25 of 35	ENSP00000498543.1

Frequencies

GnomAD3 genomes AF: 0.00736 AC: 1111 AN: 150896 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.0259

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00217

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: 0.0000592

Gnomad OTH AF: 0.00576

GnomAD2 exomes AF: 0.00177 AC: 328 AN: 185194 AF XY: 0.00115

Gnomad AFR exome AF: 0.0292

Gnomad AMR exome AF: 0.000773

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000385

Gnomad OTH exome AF: 0.00103

GnomAD4 exome AF: 0.000715 AC: 1021 AN: 1428506 Hom.: 15 Cov.: 45 AF XY: 0.000575 AC XY: 407 AN XY: 707854

African (AFR) AF: 0.0272 AC: 895 AN: 32964

American (AMR) AF: 0.00115 AC: 44 AN: 38360

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25470

East Asian (EAS) AF: 0.00 AC: 0 AN: 37982

South Asian (SAS) AF: 0.00 AC: 0 AN: 83042

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48520

Middle Eastern (MID) AF: 0.000877 AC: 5 AN: 5702

European-Non Finnish (NFE) AF: 0.0000100 AC: 11 AN: 1097372

Other (OTH) AF: 0.00112 AC: 66 AN: 59094

GnomAD4 genome AF: 0.00736 AC: 1111 AN: 151014 Hom.: 7 Cov.: 32 AF XY: 0.00717 AC XY: 529 AN XY: 73818

African (AFR) AF: 0.0259 AC: 1062 AN: 41082

American (AMR) AF: 0.00217 AC: 33 AN: 15226

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3458

East Asian (EAS) AF: 0.00 AC: 0 AN: 5112

South Asian (SAS) AF: 0.00 AC: 0 AN: 4782

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10502

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000592 AC: 4 AN: 67550

Other (OTH) AF: 0.00570 AC: 12 AN: 2104

Alfa AF: 0.000720 Hom.: 0

Bravo AF: 0.00850

ESP6500AA AF: 0.0244 AC: 99

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00171 AC: 200

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	AGRN-related disorder (1)
-	-	1	Congenital myasthenic syndrome 8 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	16
DANN	Benign	0.93
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.78	T
MetaRNN	Benign	0.0061	T
MetaSVM	Benign	-0.51	T
MutationAssessor	Benign	0.41	N
PhyloP100		0.43
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.29
Sift	Benign	0.21	T
Sift4G	Benign	0.22	T
Vest4		0.27
MutPred		0.36		Gain of catalytic residue at L1567 (P = 0.0732)
MVP		0.91
MPC		0.15
ClinPred		0.0025	T
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.59
Mutation Taster		=87/13	polymorphism

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

Other links and lift over

dbSNP: rs199876002; hg19: chr1-985126;