rs1045142

chr18-20954851-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP2

The NM_005406.3(ROCK1):c.3785G>A(p.Arg1262Gln) variant causes a missense change involving the alteration of a conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ROCK1 NM_005406.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.85

Genes affected

ROCK1 (HGNC:10251): (Rho associated coiled-coil containing protein kinase 1) This gene encodes a protein serine/threonine kinase that is activated when bound to the GTP-bound form of Rho. The small GTPase Rho regulates formation of focal adhesions and stress fibers of fibroblasts, as well as adhesion and aggregation of platelets and lymphocytes by shuttling between the inactive GDP-bound form and the active GTP-bound form. Rho is also essential in cytokinesis and plays a role in transcriptional activation by serum response factor. This protein, a downstream effector of Rho, phosphorylates and activates LIM kinase, which in turn, phosphorylates cofilin, inhibiting its actin-depolymerizing activity. A pseudogene, related to this gene, is also located on chromosome 18. [provided by RefSeq, Aug 2015]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PP2: Missense variant where missense usually causes diseases, ROCK1

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ROCK1	NM_005406.3	c.3785G>A	p.Arg1262Gln	missense_variant	31/33	ENST00000399799.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ROCK1	ENST00000399799.3	c.3785G>A	p.Arg1262Gln	missense_variant	31/33	1	NM_005406.3	P1
ROCK1	ENST00000578051.1	c.20G>A	p.Arg7Gln	missense_variant	1/2	2
ROCK1	ENST00000635540.2	c.*420G>A		3_prime_UTR_variant, NMD_transcript_variant	32/34	5
ROCK1	ENST00000584687.1			downstream_gene_variant		4

Frequencies

GnomAD3 genomes AF: 0.00 AC: 19 AN: 147664 Hom.: 0 Cov.: 33 FAILED QC

Gnomad AFR AF: 0.0000251

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000672

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000615

Gnomad SAS AF: 0.000218

Gnomad FIN AF: 0.000392

Gnomad MID AF: 0.00329

Gnomad NFE AF: 0.000120

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000205 AC: 3 AN: 1460866 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 726750

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000129 AC: 19 AN: 147776 Hom.: 0 Cov.: 33 AF XY: 0.000152 AC XY: 11 AN XY: 72222

Gnomad4 AFR AF: 0.0000251

Gnomad4 AMR AF: 0.0000671

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000616

Gnomad4 SAS AF: 0.000218

Gnomad4 FIN AF: 0.000392

Gnomad4 NFE AF: 0.000120

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000429 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Uncertain	0.099	D
BayesDel_noAF	Benign	-0.10
Cadd	Pathogenic	33
Dann	Uncertain	0.99
DEOGEN2	Benign	0.24	T;.
Eigen	Uncertain	0.64
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	D;D
M_CAP	Benign	0.023	T
MetaRNN	Uncertain	0.63	D;D
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.6	L;.
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-2.5	D;.
REVEL	Benign	0.23
Sift	Benign	0.059	T;.
Sift4G	Benign	0.23	T;D
Polyphen		0.95	P;.
Vest4		0.52
MutPred		0.49		Gain of ubiquitination at K1267 (P = 0.0411);.;
MVP		0.71
MPC		2.5
ClinPred		0.97	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.37
gMVP		0.55

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: rs1045142; hg19: chr18-18534812; COSMIC: COSV67695445; COSMIC: COSV67695445;