rs1222969937

Variant names:

• chr22-30285682-C-T
• rs1222969937
• NM_001037666.3:c.928G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001037666.3(CASTOR1):​c.928G>A​(p.Glu310Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000383 in 1,566,356 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: CASTOR1 NM_001037666.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.50
• 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.42145193).

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.928G>A	p.Glu310Lys	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.928G>A	p.Glu310Lys	missense	Exon 9 of 9	ENSP00000384183.4	Q8WTX7
	ENSG00000248751	ENST00000434291.5	TSL:2	c.1381G>A	p.Glu461Lys	missense	Exon 13 of 13	ENSP00000401535.1	H7C1Q1
	CASTOR1	ENST00000865129.1		c.991G>A	p.Glu331Lys	missense	Exon 9 of 9	ENSP00000535188.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152142 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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000354 AC: 5 AN: 1414214 Hom.: 0 Cov.: 31 AF XY: 0.00000286 AC XY: 2 AN XY: 699214

African (AFR) AF: 0.00 AC: 0 AN: 32438

American (AMR) AF: 0.00 AC: 0 AN: 38246

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25314

East Asian (EAS) AF: 0.00 AC: 0 AN: 37216

South Asian (SAS) AF: 0.00 AC: 0 AN: 80504

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49290

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4932

European-Non Finnish (NFE) AF: 0.00000368 AC: 4 AN: 1087764

Other (OTH) AF: 0.0000171 AC: 1 AN: 58510

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152142 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 74308

African (AFR) AF: 0.00 AC: 0 AN: 41442

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000378

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	Pathogenic	0.72
BayesDel_addAF	Benign	-0.021	T
BayesDel_noAF	Benign	-0.27
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.032	T
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.068	D
MetaRNN	Benign	0.42	T
MetaSVM	Benign	-1.1	T
PhyloP100		4.5
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.22
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.27
MVP		0.42
MPC		1.5
ClinPred		0.99	D
GERP RS		4.1
Varity_R		0.87
gMVP		0.80
Mutation Taster		=58/42	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: rs1222969937; hg19: chr22-30681671; COSMIC: COSV57574729; COSMIC: COSV57574729;