rs142440782

Positions:

• chr1-1043572-C-G
• chr1-1043572-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_198576.4(AGRN):​c.1638C>G​(p.Cys546Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000207 in 1,452,774 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. C546C) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: AGRN NM_198576.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.18

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.961

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AGRN	NM_198576.4	c.1638C>G	p.Cys546Trp	missense_variant	9/36	ENST00000379370.7	NP_940978.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AGRN	ENST00000379370.7	c.1638C>G	p.Cys546Trp	missense_variant	9/36	1	NM_198576.4	ENSP00000368678.2
AGRN	ENST00000651234.1	c.1323C>G	p.Cys441Trp	missense_variant	8/38			ENSP00000499046.1
AGRN	ENST00000652369.1	c.1323C>G	p.Cys441Trp	missense_variant	8/35			ENSP00000498543.1
AGRN	ENST00000620552.4	c.1224C>G	p.Cys408Trp	missense_variant	9/39	5		ENSP00000484607.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000419 AC: 1 AN: 238448 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 130406

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000928

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000207 AC: 3 AN: 1452774 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 723146

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Benign	0.77
DANN	Uncertain	0.97
Eigen	Benign	-0.75
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.094	N
LIST_S2	Uncertain	0.88	D;D
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Uncertain	0.18	D
MutationAssessor	Uncertain	2.4	M;.
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-8.7	D;.
REVEL	Uncertain	0.58
Sift	Uncertain	0.0010	D;.
Sift4G	Uncertain	0.0030	D;D
Vest4		0.95
MutPred		0.70		Loss of disorder (P = 0.0061);.;
MVP		0.75
MPC		0.63
ClinPred		0.85	D
GERP RS		-7.3
gMVP		0.94

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

Publications

LitVar

Other links and lift over

dbSNP: rs142440782; hg19: chr1-978952;