2-74426325-G-C

Position:

• chr2-74426325-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001015055.2(RTKN):​c.1610C>G​(p.Pro537Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P537H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: RTKN NM_001015055.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.10

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

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2689969).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RTKN	NM_001015055.2	c.1610C>G	p.Pro537Arg	missense_variant	12/12	ENST00000272430.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RTKN	ENST00000272430.10	c.1610C>G	p.Pro537Arg	missense_variant	12/12	1	NM_001015055.2	P4
RTKN	ENST00000233330.6	c.1460C>G	p.Pro487Arg	missense_variant	12/12	1
RTKN	ENST00000305557.9	c.1571C>G	p.Pro524Arg	missense_variant	13/13	5		A1
RTKN	ENST00000640304.2	c.*322C>G		3_prime_UTR_variant	12/12	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

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

Aug 01, 2022

The c.1610C>G (p.P537R) alteration is located in exon 12 (coding exon 12) of the RTKN gene. This alteration results from a C to G substitution at nucleotide position 1610, causing the proline (P) at amino acid position 537 to be replaced by an arginine (R). 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	0.099
BayesDel_addAF	Benign	-0.033	T
BayesDel_noAF	Benign	-0.29
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	.;T;.
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.85	T;T;T
M_CAP	Benign	0.0068	T
MetaRNN	Benign	0.27	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	2.0	.;M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-2.9	D;D;D
REVEL	Benign	0.15
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.012	D;D;D
Polyphen		0.99	D;D;.
Vest4		0.25
MutPred		0.30		.;Gain of MoRF binding (P = 5e-04);.;
MVP		0.72
MPC		0.38
ClinPred		0.98	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.46
gMVP		0.45

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs372468955; hg19: chr2-74653452;