chr2-27858572-C-G

Position:

• chr2-27858572-C-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_022128.3(RBKS):​c.90-1G>C variant causes a splice acceptor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00846 in 1,609,536 control chromosomes in the GnomAD database, including 86 homozygotes. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0062 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0087 (82 hom.)
• Consequence: RBKS NM_022128.3 splice_acceptor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 7.51

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 Likely_benign. Variant got -4 ACMG points.

• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RBKS	NM_022128.3	c.90-1G>C		splice_acceptor_variant		ENST00000302188.8
RBKS	NM_001287580.2	c.-112-1G>C		splice_acceptor_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RBKS	ENST00000302188.8	c.90-1G>C		splice_acceptor_variant		1	NM_022128.3	P1
RBKS	ENST00000449378.1	c.*1017-1G>C		splice_acceptor_variant, NMD_transcript_variant		1
MRPL33	ENST00000448427.1	c.165-35961C>G		intron_variant, NMD_transcript_variant		4
RBKS	ENST00000453412.1	c.*113-1G>C		splice_acceptor_variant, NMD_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00619 AC: 941 AN: 152046 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00162

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.00548

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00974

Gnomad FIN AF: 0.00765

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00990

Gnomad OTH AF: 0.00621

GnomAD3 exomes AF: 0.00701 AC: 1738 AN: 247880 Hom.: 16 AF XY: 0.00729 AC XY: 978 AN XY: 134238

Gnomad AFR exome AF: 0.00155

Gnomad AMR exome AF: 0.00162

Gnomad ASJ exome AF: 0.00796

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00871

Gnomad FIN exome AF: 0.00835

Gnomad NFE exome AF: 0.00968

Gnomad OTH exome AF: 0.00770

GnomAD4 exome AF: 0.00870 AC: 12681 AN: 1457372 Hom.: 82 Cov.: 30 AF XY: 0.00880 AC XY: 6379 AN XY: 725290

Gnomad4 AFR exome AF: 0.000879

Gnomad4 AMR exome AF: 0.00210

Gnomad4 ASJ exome AF: 0.00644

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00850

Gnomad4 FIN exome AF: 0.00864

Gnomad4 NFE exome AF: 0.00965

Gnomad4 OTH exome AF: 0.00794

GnomAD4 genome AF: 0.00619 AC: 942 AN: 152164 Hom.: 4 Cov.: 32 AF XY: 0.00571 AC XY: 425 AN XY: 74376

Gnomad4 AFR AF: 0.00161

Gnomad4 AMR AF: 0.00262

Gnomad4 ASJ AF: 0.00548

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00996

Gnomad4 FIN AF: 0.00765

Gnomad4 NFE AF: 0.00990

Gnomad4 OTH AF: 0.00615

Alfa AF: 0.00827 Hom.: 3

Bravo AF: 0.00538

TwinsUK AF: 0.0116 AC: 43

ALSPAC AF: 0.00623 AC: 24

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.0101 AC: 87

ExAC AF: 0.00698 AC: 848

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00824

EpiControl AF: 0.00759

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2024

RBKS: BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	26
DANN	Uncertain	0.99
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
MutationTaster	Benign	1.0	D;D
GERP RS		5.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.90
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.27		Position offset: -30
DS_AL_spliceai		0.99		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs140948699; hg19: chr2-28081439; COSMIC: COSV99043004;