2-27781671-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_022128.3(RBKS):​c.913G>A​(p.Ala305Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000923 in 1,613,994 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000099 ( 0 hom. )

Consequence

RBKS
NM_022128.3 missense

Scores

19

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -1.41
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.02163747).
BP6
Variant 2-27781671-C-T is Benign according to our data. Variant chr2-27781671-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3787390.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RBKSNM_022128.3 linkc.913G>A p.Ala305Thr missense_variant Exon 8 of 8 ENST00000302188.8 NP_071411.1 Q9H477-1
RBKSNM_001287580.2 linkc.712G>A p.Ala238Thr missense_variant Exon 9 of 9 NP_001274509.1 Q9H477

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RBKSENST00000302188.8 linkc.913G>A p.Ala305Thr missense_variant Exon 8 of 8 1 NM_022128.3 ENSP00000306817.3 Q9H477-1
RBKSENST00000449378.1 linkn.*1840G>A non_coding_transcript_exon_variant Exon 9 of 9 1 ENSP00000413789.1 E7EQ18
RBKSENST00000449378.1 linkn.*1840G>A 3_prime_UTR_variant Exon 9 of 9 1 ENSP00000413789.1 E7EQ18
MRPL33ENST00000448427.1 linkn.42-901C>T intron_variant Intron 2 of 5 4 ENSP00000407385.1 F8WF37

Frequencies

GnomAD3 genomes
AF:
0.0000329
AC:
5
AN:
152124
Hom.:
0
Cov.:
32
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:
0.000828
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000159
AC:
40
AN:
251306
Hom.:
0
AF XY:
0.000236
AC XY:
32
AN XY:
135822
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000579
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00121
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000880
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000985
AC:
144
AN:
1461752
Hom.:
0
Cov.:
30
AF XY:
0.000135
AC XY:
98
AN XY:
727182
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000447
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00123
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000171
Gnomad4 OTH exome
AF:
0.000282
GnomAD4 genome
AF:
0.0000328
AC:
5
AN:
152242
Hom.:
0
Cov.:
32
AF XY:
0.0000537
AC XY:
4
AN XY:
74436
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:
0.000829
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000277
Hom.:
0
Bravo
AF:
0.00000378
ExAC
AF:
0.000198
AC:
24
Asia WGS
AF:
0.00115
AC:
4
AN:
3478
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Likely benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Benign:1
Feb 18, 2025
Ambry Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.098
BayesDel_addAF
Benign
-0.53
T
BayesDel_noAF
Benign
-0.58
CADD
Benign
3.8
DANN
Benign
0.67
DEOGEN2
Benign
0.33
T
Eigen
Benign
-1.1
Eigen_PC
Benign
-1.1
FATHMM_MKL
Benign
0.062
N
LIST_S2
Benign
0.79
T
M_CAP
Benign
0.0056
T
MetaRNN
Benign
0.022
T
MetaSVM
Benign
-0.97
T
MutationAssessor
Benign
1.5
L
PrimateAI
Benign
0.21
T
PROVEAN
Benign
-0.53
N
REVEL
Benign
0.10
Sift
Benign
0.64
T
Sift4G
Benign
0.59
T
Polyphen
0.0010
B
Vest4
0.057
MutPred
0.34
Gain of glycosylation at A305 (P = 0.0994);
MVP
0.42
MPC
0.034
ClinPred
0.011
T
GERP RS
-2.0
Varity_R
0.12
gMVP
0.30

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.

Other links and lift over

dbSNP: rs561365833; hg19: chr2-28004538; API