2-74426572-T-C

Variant names:

• chr2-74426572-T-C
• rs757566412
• NM_001015055.2:c.1363A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001015055.2(RTKN):​c.1363A>G​(p.Ile455Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000157 in 1,525,074 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000073 (0 hom.)
• Consequence: RTKN NM_001015055.2 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.67
• Publications: 0 publications found

Genes affected

RTKN (HGNC:10466): (rhotekin) This gene encodes a scaffold protein that interacts with GTP-bound Rho proteins. Binding of this protein inhibits the GTPase activity of Rho proteins. This protein may interfere with the conversion of active, GTP-bound Rho to the inactive GDP-bound form by RhoGAP. Rho proteins regulate many important cellular processes, including cytokinesis, transcription, smooth muscle contraction, cell growth and transformation. Dysregulation of the Rho signal transduction pathway has been implicated in many forms of cancer. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.23517546).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RTKN	NM_001015055.2	c.1363A>G	p.Ile455Val	missense_variant, splice_region_variant	Exon 12 of 12	ENST00000272430.10	NP_001015055.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RTKN	ENST00000272430.10	c.1363A>G	p.Ile455Val	missense_variant, splice_region_variant	Exon 12 of 12	1	NM_001015055.2	ENSP00000272430.5

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152110 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000917

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000170 AC: 3 AN: 176100 AF XY: 0.0000212

Gnomad AFR exome AF: 0.0000738

Gnomad AMR exome AF: 0.0000831

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000728 AC: 10 AN: 1372964 Hom.: 0 Cov.: 32 AF XY: 0.00000149 AC XY: 1 AN XY: 672232

African (AFR) AF: 0.0000647 AC: 2 AN: 30926

American (AMR) AF: 0.000151 AC: 5 AN: 33178

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20446

East Asian (EAS) AF: 0.00 AC: 0 AN: 38502

South Asian (SAS) AF: 0.00 AC: 0 AN: 72484

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49560

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4970

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1066388

Other (OTH) AF: 0.0000531 AC: 3 AN: 56510

GnomAD4 genome AF: 0.0000920 AC: 14 AN: 152110 Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8 AN XY: 74302

African (AFR) AF: 0.00 AC: 0 AN: 41408

American (AMR) AF: 0.000917 AC: 14 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68008

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000200

ExAC AF: 0.00000845 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 04, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1363A>G (p.I455V) alteration is located in exon 12 (coding exon 12) of the RTKN gene. This alteration results from a A to G substitution at nucleotide position 1363, causing the isoleucine (I) at amino acid position 455 to be replaced by a valine (V). 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	0.19
BayesDel_addAF	Uncertain	0.048	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.17	.;T;.
Eigen	Benign	-0.057
Eigen_PC	Benign	0.046
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.85	D;D;D
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.24	T;T;T
MetaSVM	Benign	-0.59	T
MutationAssessor	Uncertain	2.5	.;M;.
PhyloP100		2.7
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.72	N;N;N
REVEL	Uncertain	0.34
Sift	Benign	0.034	D;D;D
Sift4G	Uncertain	0.059	T;T;T
Polyphen		0.43	B;B;.
Vest4		0.38
MutPred		0.61		.;Gain of sheet (P = 0.0125);.;
MVP		0.79
MPC		0.21
ClinPred		0.15	T
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.14
gMVP		0.35
Mutation Taster		=90/10	polymorphism

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

Other links and lift over

dbSNP: rs757566412; hg19: chr2-74653699;