22-30287449-C-G

Variant names:

• chr22-30287449-C-G
• rs368955430
• NM_001037666.3:c.296G>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_001037666.3(CASTOR1):​c.296G>C​(p.Arg99Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 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. R99C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CASTOR1 NM_001037666.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.28
• Publications: 0 publications found

Genes affected

CASTOR1 (HGNC:34423): (cytosolic arginine sensor for mTORC1 subunit 1) Enables arginine binding activity and identical protein binding activity. Involved in cellular response to L-arginine and negative regulation of TORC1 signaling. Located in cytosol. Colocalizes with GATOR2 complex. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000248751 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM1: In a mutagenesis_site No effect on interaction with the GATOR2 complex. (size 0) in uniprot entity CAST1_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37044126).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001037666.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASTOR1	NM_001037666.3	MANE Select	c.296G>C	p.Arg99Pro	missense	Exon 3 of 9	NP_001032755.1	Q8WTX7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASTOR1	ENST00000407689.8	TSL:1 MANE Select	c.296G>C	p.Arg99Pro	missense	Exon 3 of 9	ENSP00000384183.4	Q8WTX7
	ENSG00000248751	ENST00000434291.5	TSL:2	c.863G>C	p.Arg288Pro	missense	Exon 8 of 13	ENSP00000401535.1	H7C1Q1
	CASTOR1	ENST00000471480.6	TSL:1	n.274G>C		non_coding_transcript_exon	Exon 2 of 3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	T
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.37	T
MetaSVM	Benign	-1.2	T
PhyloP100		3.3
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.12
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.97	D
Vest4		0.63
MutPred		0.49		Loss of helix (P = 0.0237)
MVP		0.37
MPC		1.5
ClinPred		0.95	D
GERP RS		4.5
Varity_R		0.95
gMVP		0.95
Mutation Taster		=53/47	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: rs368955430; hg19: chr22-30683438;