chr2-74426572-T-A

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001015055.2(RTKN):​c.1363A>T​(p.Ile455Phe) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000262 in 1,525,074 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I455V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: RTKN NM_001015055.2 missense, splice_region
• Clinical Significance: Not reported in ClinVar
• 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.795

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RTKN	NM_001015055.2	c.1363A>T	p.Ile455Phe	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>T	p.Ile455Phe	missense_variant, splice_region_variant	Exon 12 of 12	1	NM_001015055.2	ENSP00000272430.5

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152110 Hom.: 0 Cov.: 32

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: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000219 AC: 3 AN: 1372964 Hom.: 0 Cov.: 32 AF XY: 0.00000149 AC XY: 1 AN XY: 672232

African (AFR) AF: 0.00 AC: 0 AN: 30926

American (AMR) AF: 0.00 AC: 0 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: 0.00000281 AC: 3 AN: 1066388

Other (OTH) AF: 0.00 AC: 0 AN: 56510

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152110 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74302

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

American (AMR) AF: 0.00 AC: 0 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: 0.0000147 AC: 1 AN: 68008

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

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.31	.;T;.
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.89	D;D;D
M_CAP	Uncertain	0.098	D
MetaRNN	Pathogenic	0.79	D;D;D
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Uncertain	2.5	.;M;.
PhyloP100		2.7
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-2.8	D;D;D
REVEL	Uncertain	0.61
Sift	Uncertain	0.0020	D;D;D
Sift4G	Uncertain	0.0040	D;D;D
Polyphen		0.99	D;D;.
Vest4		0.69
MutPred		0.58		.;Loss of catalytic residue at P457 (P = 0.0354);.;
MVP		0.87
MPC		0.63
ClinPred		0.96	D
GERP RS		4.0
Varity_R		0.42
gMVP		0.64
Mutation Taster		=61/39	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;