22-30285658-C-T

Variant names:

• chr22-30285658-C-T
• rs201767342
• NM_001037666.3:c.952G>A

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.952G>A​(p.Glu318Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000464 in 1,572,130 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E318Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000049 (0 hom.)
• Consequence: CASTOR1 NM_001037666.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.776
• Publications: 1 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=0.054188997).

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.952G>A	p.Glu318Lys	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.952G>A	p.Glu318Lys	missense	Exon 9 of 9	ENSP00000384183.4	Q8WTX7
	ENSG00000248751	ENST00000434291.5	TSL:2	c.1405G>A	p.Glu469Lys	missense	Exon 13 of 13	ENSP00000401535.1	H7C1Q1
	CASTOR1	ENST00000865129.1		c.1015G>A	p.Glu339Lys	missense	Exon 9 of 9	ENSP00000535188.1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152140 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000109 AC: 2 AN: 182732 AF XY: 0.0000101

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000261

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000486 AC: 69 AN: 1419990 Hom.: 0 Cov.: 31 AF XY: 0.0000384 AC XY: 27 AN XY: 702802

African (AFR) AF: 0.0000307 AC: 1 AN: 32614

American (AMR) AF: 0.00 AC: 0 AN: 39300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25378

East Asian (EAS) AF: 0.00 AC: 0 AN: 37472

South Asian (SAS) AF: 0.00 AC: 0 AN: 80918

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49372

Middle Eastern (MID) AF: 0.000224 AC: 1 AN: 4456

European-Non Finnish (NFE) AF: 0.0000605 AC: 66 AN: 1091800

Other (OTH) AF: 0.0000170 AC: 1 AN: 58680

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152140 Hom.: 0 Cov.: 34 AF XY: 0.0000269 AC XY: 2 AN XY: 74312

African (AFR) AF: 0.00 AC: 0 AN: 41436

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000340

ExAC AF: 0.0000339 AC: 4

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	15
DANN	Uncertain	0.97
DEOGEN2	Benign	0.011	T
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.049	N
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.0098	T
MetaRNN	Benign	0.054	T
MetaSVM	Benign	-0.93	T
PhyloP100		0.78
PROVEAN	Benign	-0.74	N
REVEL	Benign	0.016
Sift	Benign	0.63	T
Sift4G	Benign	0.78	T
Polyphen		0.51	P
Vest4		0.12
MutPred		0.28		Gain of ubiquitination at E318 (P = 0.0198)
MVP		0.18
MPC		0.56
ClinPred		0.77	D
GERP RS		1.9
Varity_R		0.19
gMVP		0.48
Mutation Taster		=76/24	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: rs201767342; hg19: chr22-30681647;