chr1-1050054-T-C

Variant names:

• chr1-1050054-T-C
• rs535286672
• NM_198576.4:c.4879+17T>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_198576.4(AGRN):​c.4879+17T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 732,118 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.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: AGRN NM_198576.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.260
• Publications: 0 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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGRN	NM_198576.4	c.4879+17T>C		intron_variant	Intron 27 of 35	ENST00000379370.7	NP_940978.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGRN	ENST00000379370.7	c.4879+17T>C		intron_variant	Intron 27 of 35	1	NM_198576.4	ENSP00000368678.2
AGRN	ENST00000651234.1	c.4564+17T>C		intron_variant	Intron 26 of 37			ENSP00000499046.1
AGRN	ENST00000652369.2	c.4564+17T>C		intron_variant	Intron 26 of 34			ENSP00000498543.1
AGRN	ENST00000620552.4	c.4465+17T>C		intron_variant	Intron 27 of 38	5		ENSP00000484607.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 127822 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 1 AN: 732118 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 376690

⚠️ 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: 12528

American (AMR) AF: 0.00 AC: 0 AN: 31376

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17116

East Asian (EAS) AF: 0.00 AC: 0 AN: 20714

South Asian (SAS) AF: 0.00 AC: 0 AN: 67286

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33894

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2656

European-Non Finnish (NFE) AF: 0.00000194 AC: 1 AN: 515518

Other (OTH) AF: 0.00 AC: 0 AN: 31030

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 127822 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 61874

African (AFR) AF: 0.00 AC: 0 AN: 29740

American (AMR) AF: 0.00 AC: 0 AN: 13386

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3220

East Asian (EAS) AF: 0.00 AC: 0 AN: 3756

South Asian (SAS) AF: 0.00 AC: 0 AN: 3692

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8440

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 298

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 62650

Other (OTH) AF: 0.00 AC: 0 AN: 1782

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.5
DANN	Benign	0.19
PhyloP100		-0.26

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: rs535286672; hg19: chr1-985434;