rs140764403

Positions:

• chr1-1045172-G-A
• chr1-1045172-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_198576.4(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. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00091 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00092 (7 hom.)
• Consequence: AGRN NM_198576.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.00700

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 -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 [Likely_benign]. Clinvar id 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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AGRN	NM_198576.4	c.2266G>A	p.Ala756Thr	missense_variant	13/36	ENST00000379370.7	NP_940978.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AGRN	ENST00000379370.7	c.2266G>A	p.Ala756Thr	missense_variant	13/36	1	NM_198576.4	ENSP00000368678	P1
AGRN	ENST00000651234.1	c.1951G>A	p.Ala651Thr	missense_variant	12/38			ENSP00000499046
AGRN	ENST00000652369.1	c.1951G>A	p.Ala651Thr	missense_variant	12/35			ENSP00000498543
AGRN	ENST00000620552.4	c.1852G>A	p.Ala618Thr	missense_variant	13/39	5		ENSP00000484607

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

GnomAD3 exomes AF: 0.00123 AC: 303 AN: 245504 Hom.: 1 AF XY: 0.00134 AC XY: 179 AN XY: 133562

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 SAS exome AF: 0.000719

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

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.000380

Gnomad4 ASJ exome AF: 0.00249

Gnomad4 EAS exome AF: 0.00781

Gnomad4 SAS exome AF: 0.000940

Gnomad4 FIN exome AF: 0.00368

Gnomad4 NFE exome AF: 0.000472

Gnomad4 OTH exome AF: 0.00136

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

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00541

Gnomad4 SAS AF: 0.00186

Gnomad4 FIN AF: 0.00273

Gnomad4 NFE AF: 0.000735

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000919 Hom.: 1

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

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 12, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 19, 2024	Variant summary: AGRN c.2266G>A (p.Ala756Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00088 in 1,605,666 control chromosomes in the gnomAD database, including 6 homozygotes in the gnomAD database (v4 dataset). However, the variant was reported in some East Asian subpopulations with an even higher allele frequency, e.g. in the Japanese, with an allele frequency of 0.012 (including 4 homozygotes, in the jMorp database [PMID: 33179747]). To our knowledge, no occurrence of c.2266G>A in individuals affected with &phenotype& and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 263169). Based on the evidence outlined above, the variant was classified as benign. -

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	AGRN: BP4 -

Congenital myasthenic syndrome 8 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 16, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
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;T
M_CAP	Uncertain	0.097	D
MetaRNN	Benign	0.013	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.2	L;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.45	N;.
REVEL	Benign	0.12
Sift	Benign	0.53	T;.
Sift4G	Benign	0.51	T;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

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