rs776698665

Variant names:

• chr1-1020177-C-A
• rs776698665
• NM_198576.4:c.5C>A
• AGRN p.Ala2Asp

Your query was ambiguous. Multiple possible variants found:

• chr1-1020177-C-A
• chr1-1020177-C-T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_198576.4(AGRN):​c.5C>A​(p.Ala2Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000157 in 1,334,040 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A2P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00093 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000059 (0 hom.)
• Consequence: AGRN NM_198576.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.0910
• Publications: 1 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: DEFINITIVE, STRONG Submitted by: ClinGen, 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009748369).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198576.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGRN	NM_198576.4	MANE Select	c.5C>A	p.Ala2Asp	missense	Exon 1 of 36	NP_940978.2
	AGRN	NM_001305275.2		c.5C>A	p.Ala2Asp	missense	Exon 1 of 39	NP_001292204.1	O00468-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGRN	ENST00000379370.7	TSL:1 MANE Select	c.5C>A	p.Ala2Asp	missense	Exon 1 of 36	ENSP00000368678.2	O00468-6
	AGRN	ENST00000620552.4	TSL:5	c.-410C>A		5_prime_UTR	Exon 1 of 39	ENSP00000484607.1	A0A087X208

Frequencies

GnomAD3 genomes AF: 0.000922 AC: 139 AN: 150818 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00284

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00112

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: 0.0000148

Gnomad OTH AF: 0.00193

GnomAD2 exomes AF: 0.000165 AC: 5 AN: 30378 AF XY: 0.000109

Gnomad AFR exome AF: 0.00450

Gnomad AMR exome AF: 0.000566

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000592 AC: 70 AN: 1183116 Hom.: 0 Cov.: 28 AF XY: 0.0000484 AC XY: 28 AN XY: 578676

African (AFR) AF: 0.00197 AC: 46 AN: 23296

American (AMR) AF: 0.000554 AC: 8 AN: 14448

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17094

East Asian (EAS) AF: 0.00 AC: 0 AN: 25060

South Asian (SAS) AF: 0.00 AC: 0 AN: 49140

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 27354

Middle Eastern (MID) AF: 0.000308 AC: 1 AN: 3252

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 976048

Other (OTH) AF: 0.000316 AC: 15 AN: 47424

GnomAD4 genome AF: 0.000928 AC: 140 AN: 150924 Hom.: 0 Cov.: 31 AF XY: 0.000773 AC XY: 57 AN XY: 73742

African (AFR) AF: 0.00285 AC: 118 AN: 41352

American (AMR) AF: 0.00112 AC: 17 AN: 15174

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3442

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10260

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.0000148 AC: 1 AN: 67480

Other (OTH) AF: 0.00191 AC: 4 AN: 2096

Alfa AF: 0.000569 Hom.: 0

Bravo AF: 0.00114

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Congenital myasthenic syndrome 8 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	20
DANN	Benign	0.66
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.086	N
LIST_S2	Benign	0.18	T
MetaRNN	Benign	0.0097	T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	1.1	L
PhyloP100		0.091
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-0.88	N
REVEL	Benign	0.17
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
PromoterAI		-0.22	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
gMVP		0.40
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs776698665;

hg19: chr1-955557;