rs4666020

Positions:

• chr2-27823161-G-A
• chr2-27823161-G-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_022128.3(RBKS):​c.795+4406C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.258 in 152,034 control chromosomes in the GnomAD database, including 5,962 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.26 (5962 hom., cov: 32)
• Consequence: RBKS NM_022128.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.800

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 Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.607 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RBKS	NM_022128.3	c.795+4406C>T		intron_variant		ENST00000302188.8	NP_071411.1
RBKS	NM_001287580.2	c.594+4406C>T		intron_variant			NP_001274509.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RBKS	ENST00000302188.8	c.795+4406C>T		intron_variant		1	NM_022128.3	ENSP00000306817.3
RBKS	ENST00000449378.1	n.*1722+4406C>T		intron_variant		1		ENSP00000413789.1
RBKS	ENST00000458185.1	c.375+4406C>T		intron_variant		3		ENSP00000393558.1
MRPL33	ENST00000448427.1	n.164+40467G>A		intron_variant		4		ENSP00000407385.1

Frequencies

GnomAD3 genomes AF: 0.257 AC: 39107 AN: 151916 Hom.: 5947 Cov.: 32

Gnomad AFR AF: 0.308

Gnomad AMI AF: 0.241

Gnomad AMR AF: 0.363

Gnomad ASJ AF: 0.152

Gnomad EAS AF: 0.625

Gnomad SAS AF: 0.254

Gnomad FIN AF: 0.266

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.181

Gnomad OTH AF: 0.242

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.258 AC: 39172 AN: 152034 Hom.: 5962 Cov.: 32 AF XY: 0.267 AC XY: 19826 AN XY: 74310

Gnomad4 AFR AF: 0.308

Gnomad4 AMR AF: 0.364

Gnomad4 ASJ AF: 0.152

Gnomad4 EAS AF: 0.625

Gnomad4 SAS AF: 0.253

Gnomad4 FIN AF: 0.266

Gnomad4 NFE AF: 0.181

Gnomad4 OTH AF: 0.242

Alfa AF: 0.199 Hom.: 7093

Bravo AF: 0.274

Asia WGS AF: 0.443 AC: 1534 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	18
DANN	Benign	0.57

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: rs4666020; hg19: chr2-28046028;