5-97167887-A-G

Variant names:

• chr5-97167887-A-G
• rs759975930
• NM_018343.3:c.977T>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_018343.3(RIOK2):​c.977T>C​(p.Ile326Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000089 in 1,461,062 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: RIOK2 NM_018343.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.369
• Publications: 0 publications found

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

Our verdict: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03665322).
• BP6: Variant 5-97167887-A-G is Benign according to our data. Variant chr5-97167887-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 3154469.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RIOK2	NM_018343.3	c.977T>C	p.Ile326Thr	missense_variant	Exon 8 of 10	ENST00000283109.8	NP_060813.2
RIOK2	NM_001159749.2	c.977T>C	p.Ile326Thr	missense_variant	Exon 8 of 8		NP_001153221.1
RIOK2	XM_017009628.2	c.416T>C	p.Ile139Thr	missense_variant	Exon 6 of 8		XP_016865117.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RIOK2	ENST00000283109.8	c.977T>C	p.Ile326Thr	missense_variant	Exon 8 of 10	1	NM_018343.3	ENSP00000283109.3
RIOK2	ENST00000508447.1	c.977T>C	p.Ile326Thr	missense_variant	Exon 8 of 8	1		ENSP00000420932.1
LIX1-AS1	ENST00000504578.2	n.574-15121A>G		intron_variant	Intron 3 of 6	5
RIOK2	ENST00000511012.1	c.-170T>C		upstream_gene_variant		2		ENSP00000422772.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000798 AC: 2 AN: 250472 AF XY: 0.00000738

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000890 AC: 13 AN: 1461062 Hom.: 0 Cov.: 34 AF XY: 0.00000963 AC XY: 7 AN XY: 726858

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000447 AC: 2 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52648

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00000899 AC: 10 AN: 1111976

Other (OTH) AF: 0.00 AC: 0 AN: 60384

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Dec 28, 2023

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	0.049
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.0030
DANN	Benign	0.62
DEOGEN2	Benign	0.0024	T;.
Eigen	Benign	-1.9
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.33	T;T
M_CAP	Benign	0.0018	T
MetaRNN	Benign	0.037	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.2	N;N
PhyloP100		-0.37
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.85	N;N
REVEL	Benign	0.0080
Sift	Benign	0.70	T;T
Sift4G	Benign	0.57	T;T
Polyphen		0.0	B;.
Vest4		0.020
MutPred		0.23		Gain of phosphorylation at I326 (P = 0.0071);Gain of phosphorylation at I326 (P = 0.0071);
MVP		0.26
MPC		0.18
ClinPred		0.030	T
GERP RS		-8.4
PromoterAI		0.015	Neutral
Varity_R		0.012
gMVP		0.071
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs759975930; hg19: chr5-96503591;