5-97167603-T-G

Position:

• chr5-97167603-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_018343.3(RIOK2):​c.1261A>C​(p.Asn421His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: RIOK2 NM_018343.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.955

Genes affected

RIOK2 (HGNC:18999): (RIO kinase 2) Predicted to enable protein kinase activity. Involved in several processes, including positive regulation of rRNA processing; positive regulation of ribosomal small subunit export from nucleus; and regulation of mitotic metaphase/anaphase transition. Located in cytoplasm. Part of preribosome, small subunit precursor. [provided by Alliance of Genome Resources, Apr 2022]

LIX1-AS1 (HGNC:52976): (LIX1 and RIOK2 antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08117688).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RIOK2	NM_018343.3	c.1261A>C	p.Asn421His	missense_variant	8/10	ENST00000283109.8	NP_060813.2
RIOK2	NM_001159749.2	c.1261A>C	p.Asn421His	missense_variant	8/8		NP_001153221.1
RIOK2	XM_017009628.2	c.700A>C	p.Asn234His	missense_variant	6/8		XP_016865117.1
LIX1-AS1	XR_007058883.1	n.4605-15405T>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RIOK2	ENST00000283109.8	c.1261A>C	p.Asn421His	missense_variant	8/10	1	NM_018343.3	ENSP00000283109	P1
LIX1-AS1	ENST00000504578.2	n.574-15405T>G		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

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

May 30, 2024

The c.1261A>C (p.N421H) alteration is located in exon 8 (coding exon 8) of the RIOK2 gene. This alteration results from a A to C substitution at nucleotide position 1261, causing the asparagine (N) at amino acid position 421 to be replaced by a histidine (H). 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	0.072
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	11
DANN	Benign	0.96
DEOGEN2	Benign	0.0047	T;.
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.61	T;T
M_CAP	Benign	0.0050	T
MetaRNN	Benign	0.081	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.6	M;M
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-1.3	N;N
REVEL	Benign	0.043
Sift	Benign	0.055	T;T
Sift4G	Benign	0.13	T;T
Polyphen		0.53	P;.
Vest4		0.14
MutPred		0.12		Loss of methylation at K420 (P = 0.1415);Loss of methylation at K420 (P = 0.1415);
MVP		0.45
MPC		0.21
ClinPred		0.14	T
GERP RS		0.20
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.045
gMVP		0.087

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: rs1748882714; hg19: chr5-96503307;