Genetic Variant CASTOR1:p.Glu318Lys (chr22-30285658-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_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. 12/19 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. 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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.776

Variant links:

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]

CASTOR1 links:

ENSG00000248751 (HGNC:):

ENSG00000248751 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.054188997).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASTOR1	NM_001037666.3 link	c.952G>A	p.Glu318Lys	missense_variant	Exon 9 of 9	ENST00000407689.8	NP_001032755.1	Q8WTX7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CASTOR1	ENST00000407689.8 link	c.952G>A	p.Glu318Lys	missense_variant	Exon 9 of 9	1	NM_001037666.3	ENSP00000384183.4		Q8WTX7
ENSG00000248751	ENST00000434291.5 link	c.1405G>A	p.Glu469Lys	missense_variant	Exon 13 of 13	2		ENSP00000401535.1		H7C1Q1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152140

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.0000109

AC:

AN:

182732

Hom.:

AF XY:

0.0000101

AC XY:

AN XY:

99202

show subpopulations

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 SAS 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:

AN:

1419990

Hom.:

Cov.:

AF XY:

0.0000384

AC XY:

AN XY:

702802

show subpopulations

Gnomad4 AFR exome

AF:

0.0000307

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000605

Gnomad4 OTH exome

AF:

0.0000170

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152140

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74312

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000340

ExAC

AF:

0.0000339

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.72

CADD

Benign

DANN

Uncertain

0.97

DEOGEN2

Benign

0.011

T;T;.

Eigen

Benign

-0.84

Eigen_PC

Benign

-0.82

FATHMM_MKL

Benign

0.049

LIST_S2

Benign

0.74

T;T;T

M_CAP

Benign

0.0098

MetaRNN

Benign

0.054

T;T;T

MetaSVM

Benign

-0.93

PROVEAN

Benign

-0.74

N;N;N

REVEL

Benign

0.016

Sift

Benign

0.63

T;T;T

Sift4G

Benign

0.78

T;T;T

Polyphen

0.51

P;B;.

Vest4

0.12

MutPred

0.28

Gain of ubiquitination at E318 (P = 0.0198);.;.;

MVP

0.18

MPC

0.56

ClinPred

0.77

GERP RS

1.9

Varity_R

0.19

gMVP

0.48

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over