1-1043961-G-T

Variant names:

• chr1-1043961-G-T
• rs755605232
• NM_198576.4:c.1937G>T

Variant summary

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

The NM_198576.4(AGRN):​c.1937G>T​(p.Arg646Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. R646Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: AGRN NM_198576.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.901

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 rank	MANE	Protein	UniProt
AGRN	NM_198576.4	c.1937G>T	p.Arg646Leu	missense_variant	Exon 10 of 36	ENST00000379370.7	NP_940978.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGRN	ENST00000379370.7	c.1937G>T	p.Arg646Leu	missense_variant	Exon 10 of 36	1	NM_198576.4	ENSP00000368678.2
AGRN	ENST00000651234.1	c.1622G>T	p.Arg541Leu	missense_variant	Exon 9 of 38			ENSP00000499046.1
AGRN	ENST00000652369.1	c.1622G>T	p.Arg541Leu	missense_variant	Exon 9 of 35			ENSP00000498543.1
AGRN	ENST00000620552.4	c.1523G>T	p.Arg508Leu	missense_variant	Exon 10 of 39	5		ENSP00000484607.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	17
DANN	Uncertain	1.0
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.85	T;T
M_CAP	Benign	0.038	D
MetaRNN	Uncertain	0.43	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L;.
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-4.4	D;.
REVEL	Benign	0.11
Sift	Benign	0.081	T;.
Sift4G	Uncertain	0.0040	D;D
Vest4		0.40
MutPred		0.55		Loss of loop (P = 0.1258);.;
MVP		0.64
MPC		0.56
ClinPred		0.96	D
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.67

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

Publications

LitVar

Other links and lift over

dbSNP: rs755605232; hg19: chr1-979341;