2-27843079-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_022128.3(RBKS):c.502C>T(p.Arg168Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000064 in 1,592,754 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000062 (0 hom.)
• Consequence: RBKS NM_022128.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.68

Genes affected

RBKS (HGNC:30325): (ribokinase) This gene encodes a member of the carbohydrate kinase PfkB family. The encoded protein phosphorylates ribose to form ribose-5-phosphate in the presence of ATP and magnesium as a first step in ribose metabolism. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2013]

MRPL33 (HGNC:14487): (mitochondrial ribosomal protein L33) Mammalian mitochondrial ribosomal proteins are encoded by nuclear genes and help in protein synthesis within the mitochondrion. Mitochondrial ribosomes (mitoribosomes) consist of a small 28S subunit and a large 39S subunit. They have an estimated 75% protein to rRNA composition compared to prokaryotic ribosomes, where this ratio is reversed. Another difference between mammalian mitoribosomes and prokaryotic ribosomes is that the latter contain a 5S rRNA. Among different species, the proteins comprising the mitoribosome differ greatly in sequence, and sometimes in biochemical properties, which prevents easy recognition by sequence homology. This gene encodes a 39S subunit protein. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RBKS	NM_022128.3	c.502C>T	p.Arg168Cys	missense_variant	5/8	ENST00000302188.8
RBKS	NM_001287580.2	c.301C>T	p.Arg101Cys	missense_variant	6/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RBKS	ENST00000302188.8	c.502C>T	p.Arg168Cys	missense_variant	5/8	1	NM_022128.3	P1
RBKS	ENST00000449378.1	c.*1429C>T		3_prime_UTR_variant, NMD_transcript_variant	6/9	1
RBKS	ENST00000458185.1	c.85C>T	p.Arg29Cys	missense_variant	1/4	3
MRPL33	ENST00000448427.1	c.165-51454G>A		intron_variant, NMD_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.0000789 AC: 12 AN: 152072 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000771

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000944

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000588 AC: 14 AN: 237988 Hom.: 0 AF XY: 0.0000543 AC XY: 7 AN XY: 128894

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000653

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000287

Gnomad SAS exome AF: 0.0000362

Gnomad FIN exome AF: 0.000140

Gnomad NFE exome AF: 0.0000182

Gnomad OTH exome AF: 0.000176

GnomAD4 exome AF: 0.0000625 AC: 90 AN: 1440566 Hom.: 0 Cov.: 30 AF XY: 0.0000559 AC XY: 40 AN XY: 715866

Gnomad4 AFR exome AF: 0.0000307

Gnomad4 AMR exome AF: 0.0000723

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000154

Gnomad4 SAS exome AF: 0.0000121

Gnomad4 FIN exome AF: 0.000245

Gnomad4 NFE exome AF: 0.0000500

Gnomad4 OTH exome AF: 0.000185

GnomAD4 genome AF: 0.0000788 AC: 12 AN: 152188 Hom.: 0 Cov.: 32 AF XY: 0.0000806 AC XY: 6 AN XY: 74408

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000772

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000944

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000159 Hom.: 0

Bravo AF: 0.0000340

ExAC AF: 0.0000576 AC: 7

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 14, 2023

The c.502C>T (p.R168C) alteration is located in exon 5 (coding exon 5) of the RBKS gene. This alteration results from a C to T substitution at nucleotide position 502, causing the arginine (R) at amino acid position 168 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.11
Cadd	Pathogenic	29
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.79	D
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D
M_CAP	Uncertain	0.14	D
MetaRNN	Uncertain	0.52	D
MetaSVM	Uncertain	0.43	D
MutationAssessor	Pathogenic	3.2	M
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.20	T
PROVEAN	Pathogenic	-5.5	D
REVEL	Uncertain	0.56
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.39
MVP		0.95
MPC		0.24
ClinPred		0.92	D
GERP RS		5.9
Varity_R		0.58
gMVP		0.61

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

Other links and lift over

dbSNP: rs201716905; hg19: chr2-28065946; COSMIC: COSV56221711;