1-1045172-G-A

Variant names:

• chr1-1045172-G-A
• rs140764403
• NM_198576.4:c.2266G>A

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.2266G>A​(p.Ala756Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000922 in 1,612,270 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 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. A756P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00091 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00092 (7 hom.)
• Consequence: AGRN NM_001305275.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.00700
• Publications: 5 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=0.012999803).
• BP6: Variant 1-1045172-G-A is Benign according to our data. Variant chr1-1045172-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 263169.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000906 (138/152278) while in subpopulation EAS AF = 0.00541 (28/5178). AF 95% confidence interval is 0.00384. There are 1 homozygotes in GnomAd4. There are 81 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 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.2266G>A	p.Ala756Thr	missense	Exon 13 of 36	NP_940978.2
	AGRN	NM_001305275.2		c.2266G>A	p.Ala756Thr	missense	Exon 13 of 39	NP_001292204.1
	AGRN	NM_001364727.2		c.1951G>A	p.Ala651Thr	missense	Exon 12 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.2266G>A	p.Ala756Thr	missense	Exon 13 of 36	ENSP00000368678.2
	AGRN	ENST00000651234.1		c.1951G>A	p.Ala651Thr	missense	Exon 12 of 38	ENSP00000499046.1
	AGRN	ENST00000652369.2		c.1951G>A	p.Ala651Thr	missense	Exon 12 of 35	ENSP00000498543.1

Frequencies

GnomAD3 genomes AF: 0.000900 AC: 137 AN: 152160 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00539

Gnomad SAS AF: 0.00165

Gnomad FIN AF: 0.00273

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000735

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00123 AC: 303 AN: 245504 AF XY: 0.00134

Gnomad AFR exome AF: 0.000250

Gnomad AMR exome AF: 0.000319

Gnomad ASJ exome AF: 0.00242

Gnomad EAS exome AF: 0.00355

Gnomad FIN exome AF: 0.00377

Gnomad NFE exome AF: 0.000745

Gnomad OTH exome AF: 0.00248

GnomAD4 exome AF: 0.000923 AC: 1348 AN: 1459992 Hom.: 7 Cov.: 34 AF XY: 0.000997 AC XY: 724 AN XY: 726292

African (AFR) AF: 0.000149 AC: 5 AN: 33456

American (AMR) AF: 0.000380 AC: 17 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00249 AC: 65 AN: 26130

East Asian (EAS) AF: 0.00781 AC: 310 AN: 39696

South Asian (SAS) AF: 0.000940 AC: 81 AN: 86216

European-Finnish (FIN) AF: 0.00368 AC: 192 AN: 52150

Middle Eastern (MID) AF: 0.0131 AC: 71 AN: 5400

European-Non Finnish (NFE) AF: 0.000472 AC: 525 AN: 1111932

Other (OTH) AF: 0.00136 AC: 82 AN: 60298

GnomAD4 genome AF: 0.000906 AC: 138 AN: 152278 Hom.: 1 Cov.: 33 AF XY: 0.00109 AC XY: 81 AN XY: 74458

African (AFR) AF: 0.000120 AC: 5 AN: 41546

American (AMR) AF: 0.000392 AC: 6 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3470

East Asian (EAS) AF: 0.00541 AC: 28 AN: 5178

South Asian (SAS) AF: 0.00186 AC: 9 AN: 4830

European-Finnish (FIN) AF: 0.00273 AC: 29 AN: 10620

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000735 AC: 50 AN: 68014

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.00111 Hom.: 2

Bravo AF: 0.000737

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000582 AC: 5

ExAC AF: 0.00128 AC: 155

Asia WGS AF: 0.00606 AC: 21 AN: 3478

EpiCase AF: 0.000872

EpiControl AF: 0.000771

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	Congenital myasthenic syndrome 8 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	12
DANN	Benign	0.86
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.59	T
M_CAP	Uncertain	0.097	D
MetaRNN	Benign	0.013	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.2	L
PhyloP100		-0.0070
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.45	N
REVEL	Benign	0.12
Sift	Benign	0.53	T
Sift4G	Benign	0.51	T
Vest4		0.19
MVP		0.73
MPC		0.12
ClinPred		0.00087	T
GERP RS		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.072
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs140764403; hg19: chr1-980552; COSMIC: COSV65071027; COSMIC: COSV65071027;