22-30285670-C-G

Variant names:

• chr22-30285670-C-G
• rs1263006101
• NM_001037666.3:c.940G>C

Variant summary

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

The NM_001037666.3(CASTOR1):​c.940G>C​(p.Gly314Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000705 in 1,418,178 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict 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. G314S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: CASTOR1 NM_001037666.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.540
• 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: 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 (MetaRNN=0.05490437).

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.940G>C	p.Gly314Arg	missense	Exon 9 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.940G>C	p.Gly314Arg	missense	Exon 9 of 9	ENSP00000384183.4	Q8WTX7
	ENSG00000248751	ENST00000434291.5	TSL:2	c.1393G>C	p.Gly465Arg	missense	Exon 13 of 13	ENSP00000401535.1	H7C1Q1
	CASTOR1	ENST00000865129.1		c.1003G>C	p.Gly335Arg	missense	Exon 9 of 9	ENSP00000535188.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 7.05e-7 AC: 1 AN: 1418178 Hom.: 0 Cov.: 31 AF XY: 0.00000143 AC XY: 1 AN XY: 701604

African (AFR) AF: 0.00 AC: 0 AN: 32572

American (AMR) AF: 0.00 AC: 0 AN: 38910

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25374

East Asian (EAS) AF: 0.00 AC: 0 AN: 37394

South Asian (SAS) AF: 0.00 AC: 0 AN: 80824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49482

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4656

European-Non Finnish (NFE) AF: 9.17e-7 AC: 1 AN: 1090322

Other (OTH) AF: 0.00 AC: 0 AN: 58644

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	0.97
DANN	Benign	0.94
DEOGEN2	Benign	0.0044	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.055	T
MetaSVM	Benign	-0.94	T
PhyloP100		-0.54
PROVEAN	Benign	-0.58	N
REVEL	Benign	0.033
Sift	Benign	0.28	T
Sift4G	Benign	0.47	T
Polyphen		0.11	B
Vest4		0.24
MutPred		0.18		Gain of helix (P = 0.0696)
MVP		0.18
MPC		0.69
ClinPred		0.13	T
GERP RS		-2.5
Varity_R		0.21
gMVP		0.52
Mutation Taster		=78/22	polymorphism

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: rs1263006101; hg19: chr22-30681659;