rs115173026

Variant names:

• chr1-1020217-G-A
• rs115173026
• NM_198576.4:c.45G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-1020217-G-A
• chr1-1020217-G-C
• chr1-1020217-G-T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_198576.4(AGRN):​c.45G>A​(p.Pro15Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000161 in 1,242,112 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. P15P) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000016 (0 hom.)
• Consequence: AGRN NM_198576.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.853
• Publications: 12 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: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP7: Synonymous conserved (PhyloP=0.853 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGRN	NM_198576.4	c.45G>A	p.Pro15Pro	synonymous_variant	Exon 1 of 36	ENST00000379370.7	NP_940978.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGRN	ENST00000379370.7	c.45G>A	p.Pro15Pro	synonymous_variant	Exon 1 of 36	1	NM_198576.4	ENSP00000368678.2
AGRN	ENST00000620552.4	c.-370G>A		5_prime_UTR_variant	Exon 1 of 39	5		ENSP00000484607.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000161 AC: 2 AN: 1242112 Hom.: 0 Cov.: 33 AF XY: 0.00000328 AC XY: 2 AN XY: 610244

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 24858

American (AMR) AF: 0.00 AC: 0 AN: 17006

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19988

East Asian (EAS) AF: 0.0000375 AC: 1 AN: 26660

South Asian (SAS) AF: 0.0000167 AC: 1 AN: 60004

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31736

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3572

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1007756

Other (OTH) AF: 0.00 AC: 0 AN: 50532

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0448430), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 971

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	11
DANN	Benign	0.83
PhyloP100		0.85
PromoterAI		0.017	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.4
Mutation Taster		=100/0	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: rs115173026; hg19: chr1-955597;