1-1043678-G-C

Position:

• chr1-1043678-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_198576.4(AGRN):​c.1744G>C​(p.Val582Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000207 in 1,448,590 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V582M) has been classified as Uncertain significance.

• 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: 5.22

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AGRN	NM_198576.4	c.1744G>C	p.Val582Leu	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.1744G>C	p.Val582Leu	missense_variant	9/36	1	NM_198576.4	ENSP00000368678.2
AGRN	ENST00000651234.1	c.1429G>C	p.Val477Leu	missense_variant	8/38			ENSP00000499046.1
AGRN	ENST00000652369.1	c.1429G>C	p.Val477Leu	missense_variant	8/35			ENSP00000498543.1
AGRN	ENST00000620552.4	c.1330G>C	p.Val444Leu	missense_variant	9/39	5		ENSP00000484607.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000207 AC: 3 AN: 1448590 Hom.: 0 Cov.: 35 AF XY: 0.00000139 AC XY: 1 AN XY: 721172

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.039	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	23
DANN	Uncertain	0.99
Eigen	Uncertain	0.31
Eigen_PC	Benign	0.22
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Uncertain	0.28	D
MetaRNN	Uncertain	0.74	D;D
MetaSVM	Uncertain	-0.089	T
MutationAssessor	Benign	1.5	L;.
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-1.8	N;.
REVEL	Uncertain	0.41
Sift	Benign	0.10	T;.
Sift4G	Uncertain	0.044	D;T
Vest4		0.58
MutPred		0.47		Gain of disorder (P = 0.2408);.;
MVP		0.77
MPC		0.28
ClinPred		0.86	D
GERP RS		4.0
gMVP		0.51

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: rs141661464; hg19: chr1-979058;